An Oncologist Writes 'A Biography Of Cancer'

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An Oncologist Writes 'A Biography Of Cancer'

TERRY GROSS, host:

This is FRESH AIR. I'm Terry Gross.

When the quote, "War on Cancer" started after President Nixon signed the 1971
National Cancer Act authorizing hundreds of millions of dollars for cancer
research, some scientists thought cancer could be curable within a few years.
There's been a lot of false hope and hype since then, no cure but a lot of
progress. Where are we now in the War on Cancer and can this war even be won?
Those are a couple of the questions that inspired the new book, "The Emperor of
All Maladies: A Biography of Cancer" by my guest Siddhartha Mukherjee.

As an oncologist immersed in the daily care of patients, he wanted to pull back
and research the history of cancer to better understand the illness he was
confronting and treating. Dr. Mukherjee is a cancer physician and researcher.
He's an assistant professor of medicine at Columbia University and a staff
physician at Columbia University Medical Center.

Dr. Mukherjee welcome to FRESH AIR. What did you want to get out of writing
this book as an oncologist yourself? Why is it important for you to have an
understanding of the history of cancer and why do you want your patients to
know that?

Dr. SIDDHARTHA MUKHERJEE (Assistant Professor of Medicine, Columbia
University): Well part of the reason is that, you know, I think one of the
themes in the book is that the past, particularly in medicine and science, is
always conversing with the future. There are ways in which you don't know until
you excavate the past of medicine; why we're here right now and what happens
next. I mean, Terry, you know, the book really grew out of a question that a
patient had asked me and she was a woman with abdominal cancer and I was
treating her. She had relapsed and responded and relapsed and responded and
finally she said, you know, I'm willing to go on, but before I go on I need to
know what it is that I'm battling.

And it was a very humbling moment for me because not only could I not answer
her question I couldn't point her to a book or a resource that would answer her
question in the most fundamental sense. I mean there are 5,000 books in the
world about cancer, you know, how, if you want to eat carrots, you can cure
this kind of cancer et cetera. And I actually found those books vaguely
insulting. And I also found that there was no resource, there was no history.
And so I wrote this book really because it wasn't there and it was an attempt
to try to write the history and to bring us up to the present such that we
could understand what happens in the future.

GROSS: Before we talk about the history of cancer treatments let's talk about
some of the things that your patients are up against and the brutality of some
of the treatments. You describe your work with a patient named Carla. Would you
describe the kind of cancer that she had and the incredible regimen of chemo
that she had to undergo with only a 30 percent of surviving after all that.

Dr. MUKHERJEE: So Carla has acute lymphoblastic leukemia. It's a very
aggressive form of cancer of the white blood cells. It usually presents in
young children but it can - there's a variant of it that presents in young
adults, actually even in older men and women. And Carla happened to have the
older variant, obviously. She was diagnosed when she was in her 30s. And in
children, this kind of cancer is highly curable, 80 percent curable, 90 percent
curable, depending on the circumstances. But in adults for reasons that we
still don't understand, the cure rate sinks down to in the 30s and 40 percent
range, and Carla had that variant of cancer.

The chemotherapy regimen for this cancer is extremely toxic. It is a regimen in
which we go on and on and on almost without any break combining multiple drugs,
seven or eight drugs, adding radiation in certain instances and in fact so much
so that we actually put in chemotherapy into the spinal cord in order to
prevent these white blood cells from overgrowing out in the brain. And so
that's how toxic and complicated this chemo regimen is.

GROSS: So what do you tell a patient like Carla when you know that the odds of
her surviving are 30 percent and that you're about to administer this
incredibly toxic set of chemo drugs including injections into her spine to
prevent the cancer from spreading to her brain?

Dr. MUKHERJEE: The first job you have I think is to inspire confidence in a
patient and you do that actually by being humble. This is a kind of great irony
of oncology is that the thing that really inspires confidence in patients is by
telling them exactly what is known and exactly what is unknown and trying to
lead them through that process. And in Carla's case, you know, I was a fellow
in training, one of the things that I said to her is, here's what we know.
Here's what we know will happen and then we'll sort of meet this blast of the
unknown. We won't know whether your counts respond. We won't know what happens
but when we are there we will find a way to solve that problem and we'll do it
together.

And I think that, for me at least, is very reassuring to say as a doctor and I
think, I hope, for patients, is very reassuring to hear.

GROSS: And she survived?

Dr. MUKHERJEE: Absolutely, she survives today.

GROSS: So let me ask you an honest question here. When a patient has such a
serious and hard-to-treat form of cancer and finds a doctor like you who is
obviously really smart and probably very good with a bedside manner but kind of
inexperienced because you're still a fellow at this point in the story, do they
get nervous that the doctor is young and inexperienced? Have you faced that a
lot?

Dr. MUKHERJEE: I did. I continue to face that. I mean, as it turns out, when
you're being treated at an academic medical center, the fellow is not the only
person who is taking care of you. The fellow is overseen by attendings. There's
a whole team of doctors and nurses and a whole variety of people come to allow
you to go through this, so the fellow is one part of this.

But that said, I think the fellow is a very major part of it because it's the
person whose learning curve is the most exponential. And in a sense, I always
say this, you know, to my own family, it's the person who is right at the
frontlines who actually knows the most about medicine.

When I was training in internal medicine we sometimes used to perform a
procedure in which we would put a catheter, a centralized catheter into the
heart and I would say to myself, you know, if I ever had to have it done for
myself or a loved one, the person I would choose is not the senior attending,
not the junior person in training but the fellow who has just come out of
training because they know exactly what the risks and benefits are. They've
sort of been at the frontline. They're like the soldier who has been there, who
knows trench warfare. And so in some ways I think, of course, there is a whole
team of experienced professionals who weigh in on the care but the fellow's
experience is the most acute.

GROSS: If you're just joining us my guest is Dr. Siddhartha Mukherjee. He's an
oncologist who has written a new book called, "The Emperor of All Maladies" and
it's a history of cancer.

Can you explain for us laypeople what the current understanding is of what
causes a cell to become cancerous?

Dr. MUKHERJEE: We've begun to get a glimpse of this - of this event. And what
we know about it is the following: There are - in cells, there are genes that
are present whose normal function is to regulate the growth of the metabolism
and the cell division of cells. And corruptions of these genes, mutations of
these genes essentially activate or inactivate critical processes that act like
accelerators and brakes. So to rephrase this: You can imagine the cell as a
molecular machine and cell division is one of the activities that it performs
and there are accelerators and brakes on cell division.

Now if you, by mutating genes, if you jam the accelerators or if you mess up
the brakes, then the cell doesn't know how to stop dividing and it begins to
divide incessantly. And part of that division also creates even more mutations.
Sometimes there are genes that can be mutated which can accelerate the
mutations of other genes. And this process goes on and on until you've found a
cell which is now capable of infinite cell division and does not know when to
stop dividing and that's what unleashes a cancer cell.

But that said, I think that's just the beginning of an understanding. Obviously
cancer is not just a dividing cell. It's a complex disease. It invades, it
metastasizes, it evades the immune system. And so there are many, many other
features of cancer which are still in their infancy in terms of our
understanding.

GROSS: Can you tell us about another feature of cancer that has recently been
discovered?

Dr. MUKHERJEE: Well actually, one of the most amazing - I just recently went to
a seminar, an academic seminar at Columbia in which the scientist was trying to
find out how is it that cancer evades the immune system. So he has been
obsessed with this idea for several years and has finally invented a mechanism
by which he can reactivate the host's immune system and potentially attack the
cancer.

And this is not just a kind of a fantasy but in fact one of the first such
drugs that recently was put into a clinical trial in metastatic melanoma and
was surprising effective at increasing the survival of patients with metastatic
melanoma. And he reminded me that, in fact, there has been no drug, no known
drug in the past which has increased survival of patients with metastatic
melanoma, and yet activation of the host's immune system seems to increase
survival. So that just tells us how little we know about sort of the global
qualities of cancer, about these new qualities that we're discovering.

GROSS: We're in an era where there are now some targeted drugs, drugs targeted
to specific forms of cancer and there are many more drugs in the works. I guess
the two best known targeted drugs are Herceptin and Gleevec. I'd like you to
choose one of those two drugs that's easier to describe and tell us how it
works as a targeted drug.

Dr. MUKHERJEE: So Gleevec is an excellent example of how one can target cancer
therapy. And essentially the cells that Gleevec attacks are a form of a
particular leukemia. It's called chronic myelogenous leukemia, or CML – I'll
call it CML. CML cells have an activated gene and that gene is what drives them
to proliferate pathologically, to keep dividing pathologically. And that gene
was discovered in the 1980s and it's called BCR-ABL. And essentially what
Gleevec does is that that gene makes a protein called BCR-ABL and Gleevec
essentially goes in and lodges itself into the heart of this protein, this
pathological driver of cell division and inactivates it.

There's a lovely phrase that someone used about this. A chemist said: Gleevec
is like an arrow directed at BCR-ABL's heart. And that phrase is really
memorable because essentially this little molecule goes and jams itself inside
the heart of this driver protein and essentially inactivates it and that's how
it makes it possible to kill these pathologically proliferating white cells and
that's what makes it a targeted therapy.

GROSS: So how toxic is Gleevec compared to the kind of chemo that most people
are familiar with where you lose your hair and you get nauseous and...

Dr. MUKHERJEE: It is absolutely not toxic at all. I mean, you know, there are
minor side effects of Gleevec but it's not toxic. It's amazing. If you see a
patient on - who is taking Gleevec for CML, the idea that they were going
through chemotherapy may or may not even occur to you. I mean there are side
effects of any medicine but really the non-toxicity to the rest of the body is
absolutely shocking.

GROSS: And what's amazing too, isn't this form of leukemia a very deadly form
of leukemia?

Dr. MUKHERJEE: It used to be.

GROSS: Right, right.

Dr. MUKHERJEE: It used to be. There is a very interesting quote in the book,
you know, one of the people who I interviewed in the book is Brian Druker, who
of course invented Gleevec along with a couple of other chemists at Novartis.
And Brian Druker said to me at the end of his interview, he said, you know,
he's achieved the perfect inversion of everything that an oncologist wants now
because, because patients on Gleevec are living longer and longer and longer,
the prevalence of CML is increasing.

So in other words people are living so long that you can now begin to see
people alive with CML in the world sort of taking Gleevec because you take it
chronically, and so Brian says he's achieved the perfect inversion of the goals
of an oncologist. He's increased the prevalence of cancer in the world.

GROSS: Right, right because people aren't dying.

Dr. MUKHERJEE: People aren't dying, exactly.

GROSS: Yeah.

Dr. MUKHERJEE: They're living with cancer as opposed to dying of cancer.

GROSS: So what are the implications of Gleevec for the future of cancer
treatment?

Dr. MUKHERJEE: Well the, one of the implications is that number one as Bruce
Chabner, again, who I interviewed for the book, is that, you know, Gleevec is a
little bit like, it's a little bit like the four-minute mile. So, you know,
when Roger Bannister ran the four-minute mile, before he ran the four-minute
mile people had all these theories about, you know, you can never run a four-
minute mile because your lungs can just not breathe fast enough or your legs or
your muscles are not designed - there's an intrinsic barrier to being able to
run the four-minute mile. And of course Bannister showed that that was not
true. And since then, now I don't know what the latest number is but it's
something like three minutes and few seconds.

And so what that means to us, what Gleevec means to us is much like the four-
minute mile, there's no intrinsic value to designing specific therapy. Such
therapies in proof could exist. We just have to find them. And so Gleevec
essentially opens an approach to running what people are calling oncology's
four-minute mile, which is finding specific therapies for every form of cancer.

GROSS: And this is a kind of therapy that unlike most chemo doesn't kill most
cells.

Dr. MUKHERJEE: Normal cells, that's right. So it has - and, you know, we'll go
back to the history - but it has what would be called exquisite specificity:
the idea that you would be able to kill the cancer cells while sparing normal
cells. You'd find what are called Achilles' heels of cancer cells, find exactly
those things that make cancer cells dependent on certain conditions for their
growth and you'd be able to target those specifically such that you now would
be able to kill cancer cells and spare normal cells.

GROSS: If you're just joining us my guest is Dr. Siddhartha Mukherjee. He is an
oncologist who is the author of the new book, "The Emperor of All Maladies: A
Biography of Cancer." Let's take a short break here and then we'll talk more
about the history of cancer. This is FRESH AIR.

(Soundbite of music)

GROSS: My guest is Dr. Siddhartha Mukherjee. He's the author of the new book,
"The Emperor of All Maladies: A Biography of Cancer". And he is an oncologist.
He's a cancer physician and researcher and assistant professor of medicine at
Columbia University and a staff physician at Columbia University Medical
Center.

You write in the book that when a chemo drug or the immune system attacks
cancer, that then mutant clones can resist the attack and start to grow. And
then the fittest cancer cells survive and they start reproducing. Is it similar
to the way bacteria can become resistant to antibiotics?

Dr. MUKHERJEE: That's exactly right. That's the exact analogy. In fact that's
exactly how cancer cells mutate and every round unleashes - you know, it's sort
of like, I sometimes say it's like the Galapagos trapped inside your body.
Every round unleashes yet another set of resistant cells and so forth until
you've finally got the next evolving clone of cells.

GROSS: So that must make cancer much harder to treat because you become
resistant to the treatment, no?

Dr. MUKHERJEE: That's exactly right so you have to find the treatment that will
reach that perfect balance between eliminating all cancer cells such that you
ultimately are left with none. That is the ultimate cure. But sometimes you
don't, again, sometimes you don't need to do that.

Again if you come back to Gleevec; Gleevec doesn't really eliminate cancer from
your body. What it does is it sends the cancer cells into a kind of state of
deep hibernation. It kills all the actively proliferating ones. But
interestingly, when you stop taking Gleevec you can relapse with cancer cells
that are somehow hidden somewhere in your body. It's a process we don't
understand fully.

GROSS: Why is it that breast cancer cells are different than leukemia cells and
they're different than colon cancer cells. Now, as you point out in the book,
the original idea for the War on Cancer was that cancer cells are cancer cells.
We'll figure out a way to kill all the cancer cells and therefore we will
vanquish cancer. But it turned out to not be that simple because all the
cancers have different cells.

Dr. MUKHERJEE: That's correct. I mean this is a very common question, you know,
why is it that breast cancer cells are different from leukemia cells? The
simplest answer to that question of course is that it's partly because breast
cells are different from blood cells. Our body has evolved exquisitely detailed
instructions that allow a nose cell to become a nose and that allow a blood
cell to become blood and a breast cell to become a breast cell and they are all
performing functions that are a requisite for the survival of a multi-cellular
organism called a human being.

Now that's part of the reason, of course, then that is that when a breast cell
becomes a breast cancer cell it evolves along a particular pathway but it still
retains some of the characteristics of its original precursor or ancestral
breast cell. And therefore every single tissue, every single tissue that bears
cells that divide, therefore there's a diversity of cancers that is produced.

Now that said, there are commonalities as well and one of the most amazing
things about modern or contemporary cancer genetics is that it is reorganizing
the universe of cancer in terms of peculiar and unexpected organizations. I'll
give you a good example of that. We talked a little bit about this kind of
leukemia called chronic myelogenous leukemia, or CML, and we said that there's
a mutation in a particular gene which drives this leukemia - this gene happens
to be called BCR-ABL. They're actually two genes fused together BCR and ABL
which create this mutant gene, BCR-ABL.

Now it turns out that there is a cousin gene which is active in a completely
different kind of cancer, a solid tumor that grows typically in the abdomen
called a gastrointestinal sarcoma, or a gist. You would say well there's no
relationship between a leukemia, which grows in the blood and chokes the
spleen, and a solid tumor that grows in the abdomen and doesn't resemble it
anatomically or physiologically at all. But it turns out if you lift up the
covers there are common genes, there are cousin genes that drive both of them.

Now if you hadn't uncovered the underlying genetics and reorganized the world
of cancer you'd never imagined that these are connected. And this is what's
happening overall in oncology. So in other words, a breast cancer might turn
out to have a very close resemblance with a gastric cancer but not every breast
cancer. And this kind of reorganization of cancer in terms of its internal
genetic anatomy has really changed the way we treat and approach cancer in
general.

GROSS: Is our genetic system programmed to get cancer?

Dr. MUKHERJEE: Well, you know, it's always hard to answer questions which are -
which speculate about evolution but this much is for sure: The very genes that
allow cells to proliferate, to survive, to move, to adapt to circumstances, to
resist poisons, those very genes, when they become corrupted, are genes that
are co-opted by cancer cells to become cancer.

So there is of course a deep link, and as the book suggests, if there's a
seminal discovery in oncology in the last 20 years it's exactly that. It's the
idea that cancer genes are often, this is not always true, but are often
mutated versions of normal genes. And that moment, the arrival of that moment
really chilled the world of cancer biology. The book describes that moment. It
really sent a kind of a chill down the spine of cancer biology. Because here we
were hoping that cancer would turn out to be some exogenous event, a virus or
something that could be then removed from our environment or removed from our
bodies and therefore we would be rid of it.

But the idea that cancer genes are sitting inside each and every one of our
chromosomes, just waiting to be corrupted or inactivated and thereby unleashing
cancer is of course one of the seminal ideas of oncology. But it also, it's a -
as you can imagine - a deep philosophical idea about what it means to be a
human being and how sort of the seeds of cancer are sort of already inlaid into
our chromosomes.

GROSS: My guest, Dr. Siddhartha Mukherjee, will be back in the second half of
the show. His new book is called, "The Emperor of All Maladies: A Biography of
Cancer." I'm Terry Gross and this is FRESH AIR.

(Soundbite of music)

GROSS: This is FRESH AIR. I'm Terry Gross. We're talking about the history of
cancer treatments, where we are now, and what's on the horizon with Dr.
Siddhartha Mukherjee, author of the new book "The Emperor of All Maladies: A
Biography of Cancer." Dr. Mukherjee is a cancer physician and researcher. He is
an assistant professor of medicine at Columbia University and a staff physician
at Columbia University Medical Center.

You write about how horrible cancer treatment was in the '70s and how difficult
cancer wards were and the intensity of nausea caused by the chemo drugs. Why is
it that chemo drugs - many chemo drugs don't produce that intensity of nausea
any longer?

Dr. MUKHERJEE: Well, to some extent it's because the drugs themselves have
changed and we've found ways to create variants - chemical variants of those
that don't cause that much nausea. But really, really the real secret is that
we found better newer anti-nausea medicines. The kind of anti-nausea medicines
that are deployed in the wards today are fundamentally different from the ones
that were available.

And you know, one of the things that gets ignored in the history of cancer is
the enormous role that taking care of symptoms, that palliative care has had in
this disease. Anti-nausea drugs, anti-pain medicines, psychological and
psychiatric help; antidepressants have played an enormous role in taking care
of the cancer patient, not as kind of a site of a single disease, but as a
human being in totality.

And I actually wanted to return to that history in this book and I paid a
separate tribute to Cicely Saunders, this nurse from England, who sort of
launched the palliative care movement. And Cicely Saunders had something very
evocative to say about it. She said two things. One thing is she says - well,
first of all, I wanted to emphasize the fact that palliation is not the
negative of treatment. It's not the antimatter of chemotherapy. It's
essentially part of the same problem-solving. You can't take care - even if
patients who have a treatable or curable form of cancer, you can't take care of
them without paying attention to the palliative aspects of their care. And the
second thing she said, and it's not soft medicine. This is medicine as hard-
edged, as real, as central to the care of patients.

So I think again, to come back to your question, anti-nausea medicines are just
one of several different ways that we've learned to take care of patients who
are undergoing chemotherapy.

GROSS: One of the forms of chemotherapy is the mega dose form, where you
harvest your own stem cells from your bone marrow. Stop me when I'm getting
this wrong.

Dr. MUKHERJEE: Yes. Absolutely.

GROSS: And then once those stem cells are out of your system and aren't in
danger of being killed by the chemo, you administer massive doses of chemo in
the hopes of killing the cancer cells, and then when the mega doses of chemo
are done you reintroduce the person's stem cells and, you know, hope for the
best. What's the status of that treatment now? Is that still being used a lot?
What kind of cancers is it considered most effective for?

Dr. MUKHERJEE: The major trials were run in breast cancer and then the trials
were negative. And this was a - it's a very sad episode in oncology. You know,
this episode actually is a recapitulation of the past in some ways. And it goes
back to this old theory which is that if something is good then more of that
something must be better.

And so the idea was that especially in the 1980s, the idea was that for breast
cancer we just weren't trying hard enough. If we could increase the doses of
chemotherapy, if we could muscle them up even further then we would finally
eliminate breast cancer from the body. And, of course, the reason we couldn't
do that so simply was essentially, the bone marrow of patients would give way
and the patients would die of bone marrow failure.

And so the idea that grew out of that was well, what if we just took the bone
marrow out, froze it, gave maximum dose of chemotherapy to breast cancer
patients and then reintroduce the bone marrow back. Well, now we have a perfect
solution. We can maximize chemotherapy and we can now also protect the bone
marrow.

Unfortunately, of course, it didn't work and that story is told in the book.
And it's a tragic, tragic story because there was a point of time when women
and doctors were so convinced that this would work that they almost wouldn't
participate in clinical trials. They said well, how can we possibly run a trial
on something that we know has got to work? This story carries the memory of the
kind of optimism that very quickly tips into hubris, which is so much part of
the story of cancer.

GROSS: And one of the horrible parts about this story is that there is so much
suffering involved with that treatment, because you basically have killed the
person's immune system.

Dr. MUKHERJEE: That's right.

GROSS: So what did we learn from that experiment with the mega doses of chemo
and the stem cell transplants for breast cancer patients?

Dr. MUKHERJEE: Well...

GROSS: Like what were the positive results of that? Or were there any?

Dr. MUKHERJEE: Well, we learned that it didn't work and, you know, in medicine
learning the negative is just as important as learning the positive, otherwise,
you know, our field would be strewn with - we'd only report positive results
and we'd never know what doesn't work, so that's the one thing that we learned.

I mean what else have we learned? We learned an enormous amount about the
tolerability of chemotherapy, is how much can and cannot be given to the human
body. And also, I think philosophically or I think more sort of in the history
of medicine, it represents a really important break because there's a point of
time when doctors and scientists and patients have to tell themselves, you
know, this strategy has reached a certain limit. That although these are
important drugs, there is no denying that the drugs that were discovered during
the 1960s and 1970s still play and will play an important role in the future of
cancer. And yet, what we do learn from them is that these strategies have a
limit and that it's really a call to us to invent new medicines to tackle this
disease.

GROSS: The main character, so to speak, in your book is Dr. Sidney Farber, for
whom the Dana-Farber Cancer Institute in Boston is named after. What was his
role in discovering anticancer treatment?

Dr. MUKHERJEE: Sidney Farber was a pathologist. He, in the 1940s, he was called
a doctor of the dead. He was - became particularly interested in childhood
leukemia because he was diagnosing childhood leukemia, but he had no treatment
for it. Children with childhood leukemia would live for about a week or two
weeks then they would die. It was a uniformed and lethal disease. And so Farber
became interested in an idea which he had known from other scientists, and the
idea was that the growth of normal white blood cells is dependent on a vitamin
called folic acid - a vitamin found in vegetables. And Farber began to wonder
well, if normal white cells depend on the growth of folic acid, then the
leukemia cells - leukemia is a cancer of white blood cells - the leukemia cells
become even more dependent on folic acid? And so could he use an anti-folic
acid, an antagonist of folic acid, to get remissions?

And so, a friend of his, an Indian chemist called Yella Subbarao, had a
chemical like this. And so essentially Farber got some of these chemicals and
he began to inject kids with these anti-foliates and he found remarkable,
although short, remissions. And in doing, so he sort of launched the history of
chemotherapy and the idea that he could cure cancer with chemicals alone, and
that's why he played a central role in the book.

GROSS: Now he also plays a central role because he hooked up with a wealthy
woman named Mary Lasker and together they helped get Congress to pass, and
helped get Nixon to sign, a bill creating and funding the National Cancer
institute. This was in 1971. You reprint an ad they took out in the Washington
Post in 1969 - December of 1969 that was headlined: Mr. Nixon, you can cure
cancer.

Dr. MUKHERJEE: Yes.

(Soundbite of laughter)

GROSS: So this started the official War on Cancer. And yet, the medical
community as you describe it was pretty divided about whether this war on
cancer was a good idea. Why would you think it wasn't?

Dr. MUKHERJEE: Well, the medical community was divided in part because they - a
lot of people, particularly the basic scientists thought that it was too
premature to launch a war on cancer. That if you hyped up the nation and said
well, we're going to launch - you know, one of the subtitles in that
advertisement was: Why don't we cure cancer by America's 200th birthday? What a
gift that would be. So you can imagine, there was a kind of an optimism, a kind
of a hubristic quality about this advertisement. And the medical community,
many scientists said it's just too premature. We don't know enough about the
cancer cell. It's like launching a rocket on the moon without knowing Newton's
laws.

GROSS: But didn't that money help scientists figure out what they needed to
know to start progressing?

Dr. MUKHERJEE: Absolutely. Absolutely.

GROSS: I mean you have to start someplace.

Dr. MUKHERJEE: Absolutely.

GROSS: And so wasn't that infusion of money really helpful or was it not?

Dr. MUKHERJEE: It was very helpful. But again, the money had to be directed
appropriately. And for a long time there was a big question about whether the
money should be directed towards finding more of these poisonous drugs that
basically killed cancer cells or should the money be directed more
appropriately towards basic investigations to uncover the mechanism by which
cancer became - cancer emerges - what's the right balance between those two
ideas or those two mechanisms of funding? And I think eventually that right
balance was found and the - it's the mechanistic understanding of cancer that's
really transformed our understanding of cancer today.

GROSS: If you're just joining us, my guest is Dr. Siddhartha Mukherjee. He is
an oncologist who is an assistant professor of medicine at Columbia University
and a staff physician at Columbia University Medical Center. He's written a new
book called "The Emperor of All Maladies: A Biography of Cancer." Let's take a
short break here and then we'll talk some more about cancer. This is FRESH AIR.

(Soundbite of music)

GROSS: My guest is Dr. Siddhartha Mukherjee. He's written a new book called
"The Emperor of All Maladies: A Biography of Cancer," and he is an oncologist.

Now you write about the infighting that was taking place in the '70s between
therapists using radiation and chemotherapists. What was the fight about?

Dr. MUKHERJEE: The fight about - was what - you know, everyone was trying to
find the best solution to cancer. And the surgeons, the chemotherapists and the
radiotherapists all thought they had the right answer. Now as it turned out,
none of them had the right answer, and also as it turns out, all of them needed
to collaborate with each other to treat cancer. Or to give you an example,
today breast cancer, particularly, is treated with every single one of those
modes. You have surgery followed by radiation followed by chemotherapy followed
by targeted therapy and that's what has allowed breast cancer to change from a
very lethal disease to, in some cases, a chronic disease, which is much less
lethal than it was 50 or 100 years ago. But it depends on an incredible
collaboration between every single discipline or every single sub-discipline
within oncology.

GROSS: Speaking of breast cancer, there was a period when radical mastectomies
had become the preferred method of treatment. And I want you to describe like
what a super radical mastectomy was like in, would this be the '70s or the
'80s?

Dr. MUKHERJEE: A little bit before that super radical mastectomies were
beginning to be performed. So to remind ourselves, radical mastectomy is yet
another theory of cancer in which, again, follows the dictum of if something is
good then more must be better. Radical mastectomy was invented by several
people, most notably William Halsted, on the theory that weren't cutting
enough. That somehow or the other little minute remnants of tissue were being
left behind and that if we cut more we would cure more. And so Halsted began to
excavate deeper and deeper into the breast, to cut large amounts of the breast
and the associated lymph nodes out.

And this edged further and further until you reached the super radical, the
ultra-radical mastectomy in which not only the breast but parts of, you know,
parts of the collarbone or parts of the tissue under the arm would all be
excised. It was like a macabre race to take out as much of the cancerous body
as possible so as to cure women.

GROSS: And why was that discontinued?

Dr. MUKHERJEE: Well, it was discontinued because ultimately, trials showed that
it didn't really help. In fact, as it turned out, even small tumors could
metastasize elsewhere in the body and therefore, cutting more locally didn't
save any extra lives. And it took - I mean this is an amazing thing, Terry. It
took 90 years to reach that conclusion. It took 90 years before surgeons and
chemotherapists and oncologists could collaborate with each other to launch the
kind of trials that finally showed that radical mastectomies didn't improve
survival by a month compared to a lumpectomy, plus radiation or a local
mastectomy.

GROSS: But people still have - oh a local mastectomy. Okay.

Dr. MUKHERJEE: That's correct. Yes.

GROSS: A lot of people still have local mastectomies.

Dr. MUKHERJEE: That's correct. People have local mastectomies. That's a, you
know, perfectly reasonable decision, depending on the surgeons. But the radical
mastectomy was not a local mastectomy. It involved a wide excavation of
tissues, a removal of many of the chest muscles. It removed the many nodes,
sometimes even more, as I said, sometimes more super radical forms.

GROSS: Now breast cancer is one of the cancers that we know there's a gene, the
BRCA gene. Actually, there's a couple of BRCA genes, right?

Dr. MUKHERJEE: That's correct.

GROSS: So how does that advance the possibility of treating breast cancer?

Dr. MUKHERJEE: Well, it advances in several different ways. But before we go
into the advancements you have to recognize an important fact and I, you know,
I just was recently reminded about this by Bruce Ponder, who came here from
Cambridge to talk about the BRCA genes. You know, if you take all the known
genes that we've identified which are responsible for breast cancer, we don't
even get to 50 percent of familial breast cancer. In other words, if you take
every known gene that's been identified as a risk factor for breast cancer, we
are only scratching the surface of the number of genes that are involved in
breast cancer. So BRCA1 and BRCA2 are just the beginnings of a story.

GROSS: Right. And is it helping to treat breast cancer?

Dr. MUKHERJEE: Absolutely, in two or three different ways. Number one is that
if you happen to have BRCA1 or BRCA2, your siblings and your female children
can also - and your male children - can also be found out whether they carry
this risk factor, this mutation or not, and they can undergo a variety of
things. They can be screened more intensively for the possible development of
breast cancer. Or, in more extreme circumstances, women have chosen to undergo
prophylactic mastectomies or prophylactic ovarian removals to prevent breast
cancer. And in both trials all those strategies work.

The final piece of it is that for the first time we're beginning to see
targeted therapies that particularly attack breast cancers that are mutated in
the BRCA genes. So this is - this takes advantage to the fact that if you have
a mutation in the BRCA gene then your breast cancer has certain proclivities
that normal cells don't. And, in fact, there have been therapies that are
directed against those proclivities, such as they now exploit the biology of
the BRCA gene.

GROSS: If you're just joining us, my guest is Dr. Siddhartha Mukherjee. He's an
oncologist who's the author of the new book "The Emperor of All Maladies: A
Biography of Cancer."

You've just completed a biography of cancer looking at the history of cancer.
I'm going to ask you to look ahead now a little bit...

Dr. MUKHERJEE: Mm-hmm.

GROSS: ...where your book ends. What are some of the strategies or medicines
that you are most hopeful about?

Dr. MUKHERJEE: The few things that I'm extremely hopeful about is that I think
the wealth of information that's coming out of the human genome and the cancer
genome will eventually lead to a whole new host of new medicines. That's
already started. I talked a little bit about Gleevec. We talked a little bit
about the drugs that particularly attack cells that are mutated in BRCA1, for
instance, and so forth. I think those are where the treatment is going.

Now that said, I think there's an equally important role of prevention and the
book talks about this. I think even in prevention, we are moving in a direction
in which we are integrating the insights of the genome into prevention. And by
that, I mean instead of looking for carcinogens just in the environment using
large epidemiological studies, we're beginning to look using more innovative
ways to find carcinogens in the world. How do various chemicals affect genes?
And you can all - you can do this in a Petri dish. You can essentially ask this
question: Do these chemicals mutate genes that are important in the development
of cancer? And you can make more sophisticated variations of this. You can say
well, okay, even if they don't mutate genes, do they activate certain genes?
And all of this is occurring, remember, in a Petri dish before this chemical
gets released into the real world.

So this kind of questioning I think can be - is really beneficial because you
could then potentially prevent putative carcinogens from appearing in the
world. So I think those are among the most exciting things that are happening;
targeted therapies, novel directions in prevention, and, you know, the
incredible insights from the human and the cancer genomes.

GROSS: What kind of cancer breakthrough would you most like to see in your
lifetime?

Dr. MUKHERJEE: Well, I'd like to see important breakthroughs in cancers that
are tough to treat: pancreatic cancer, esophageal cancer, some variants of
brain cancers. Those are, you know, if you think about cancer as a march of
progress, as a kind of the Pied Piper, as sort of leading out into Hamelin,
there are many cancers that have been left behind in that march. They're sort
of frozen in time and metastatic pancreatic cancer, metastatic melanoma, some
brain cancers are those. So I'd love to see those - at least something happen
in those directions.

GROSS: You describe a scene that I found so interesting. You know, you talk
about how your patients live in cancer world but you kind of live in cancer
world too because you're so obsessed with treating your patients and with
understanding how the treatments work, with learning the history of cancer for
your book. So there you are with your wife in the delivery room. She's
delivering her first baby.

(Soundbite of laughter)

Dr. MUKHERJEE: Yeah.

GROSS: You've got your scrubs on, you're asked to like cut the umbilical cord
and what goes through your mind?

Dr. MUKHERJEE: Well...

(Soundbite of laughter)

Dr. MUKHERJEE: ...I'm trying to cut the umbilical cord, but on the flipside of
my mind, it's almost a split of my right brain and my left brain, and here I am
in sort of the most glorious moment of my life, the birth of my child, and on
one side of my brain I'm saying to myself, I have got to harvest her umbilical
cord blood cells because these cells are useful in transplantations for kids
who have leukemia. So here I am, as I said, it's literally experiencing a split
brain syndrome in which I'm trying to be present emotionally in the birth of my
child and yet cancer is sitting on - back and forth in my mind and I'm trying
to harvest her umbilical cord blood cells in case, you know, I can bank them
for a future transplant for other kids with leukemia.

GROSS: Now what happens typically to the umbilical cord blood cells?

Dr. MUKHERJEE: You know, it's often, and this is the tragedy of it, it's often
flushed down the sink and often not collected all. I think, you know, we
absolutely need to have better centralized banking facilities free of charge
which allow us to bank these cells because kids with leukemia can benefit from
cord blood transplantation and they need these - these are very precious cells.

GROSS: Why are they so precious?

Dr. MUKHERJEE: Well, because they contain blood forming stem cells that can go
into the blood and create new blood. And they are so precious because they can
be transplanted into another child and give rise to the blood system of the
child and you can therefore eliminate the leukemia. And if you eliminate
leukemia you can often eliminate the normal - the child's blood stem cells and
you can replace it with the cord blood from another child, and that's why
they're incredibly precious.

GROSS: So were you able to harvest the blood stem cells from the umbilical cord
of your baby?

Dr. MUKHERJEE: I was able to harvest the cord blood cells. But I was also able,
thankfully, at the end of it all to enjoy the moment of childbirth.

GROSS: Thank you so much for talking with us.

Dr. MUKHERJEE: Thank you so much. It's a real pleasure.

GROSS: Dr. Siddhartha Mukherjee is the author of the new book "The Emperor of
All Maladies: A Biography of Cancer." You can read an excerpt on our website,
freshair.npr.org, where you can also download podcasts of our show.

Coming up, the controversy over whether Jane Austen's syntax and punctuation
are really hers or an editor's. Our linguist Geoff Nunberg weighs in.

This is FRESH AIR.
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Was Jane Austen Edited? Does It Matter?

TERRY GROSS, host:

For most readers the beauty of Jane Austen's style lies in her elegant syntax
and punctuation. Now an Oxford scholar has created a furor by suggesting that
the credit for Austen's style should really be given to the man who edited her
novels. But our linguist Geoff Nunberg is skeptical.

GEOFF NUNBERG: A storm in a teacup is the British version of the idiom, and
it's hard to imagine a more apt example than the squall that blew up recently
over the claim by the Oxford professor, Kathryn Sutherland, that Jane Austen
was actually a sloppy writer.

Sutherland was publicizing a new website that has put 1,000 pages of Austen's
manuscripts online. According to her, the manuscripts are full of faulty
spelling, break every rule of English grammar, and give no sign of the polished
punctuation we see in the novels. She concluded that Austen's prose must have
been heavily edited for publication, quite possibly by the querulous critic
William Gifford.

It's a measure of Austen's rock-star status that those claims got international
coverage as a major celebrity scandal. The BBC headed its report "Jane Austen's
Elegant Style May Not Be Hers." The French media website, Actualite, led with
"Jane Austen Massacred the English Language," and the Italian daily Il Giornale
used the headline "Austen Revised and Corrected by a Man."

Not surprisingly, those stories provoked a swell of indignation from the blogs
and websites of the Janeroots. The Janeites are the only literary cultists who
take their title from their idol's given name, and they're apt to take
criticisms of her personally. And Austen's defenders made some telling points.
For one thing, there's no evidence that any editor ever took a blue pencil to
Austen's prose, and we don't have so much as a page of the manuscripts of her
novels that she submitted to her publishers. All that Sutherland or anybody
else has to go on is the manuscripts for some teenage juvenilia and the rough
drafts of some unfinished or discarded works.

And looking at those manuscripts, I had a hard time figuring out what the big
problem was. There are some careless errors, but these are rough drafts and you
can't take off points for something that hasn't been handed in yet. And by the
standards of her time, she wasn't a bad speller. She was inconsistent about
possessives, and she sometimes put e before i in words like believe and
friendship, but you can find the same thing in the manuscripts of Byron and
Scott and Thomas Jefferson - the rules just weren't settled yet.

In fact, it's pure anachronism to describe any of these things as wrong or
incorrect; it's like calling Elizabeth Bennet a bachelorette. The modern notion
of correctness was a recent invention in Austen's time, and to people of
Austen's sort, it smacked of the schoolmaster and the social climber. My guess
is that she would have little use for people who went around clucking their
tongues over misplaced apostrophes in grocers' signs. That's the sort of
pedantry she might put in the mouth of Mr. Collins.

Punctuation was in flux, too. Modern readers will be disconcerted to see Austen
sticking a comma between a subject and verb or strewing dashes apparently at
random. But as Sutherland herself noted in an earlier book, Austen often used
punctuation to signal the rhythms of speech rather than the grammatical
structure. As it happens, Sutherland based that analysis on a book I wrote
about punctuation some years ago.

By the time Austen was writing, that rhythmic use of punctuation was yielding
to the modern system based on syntax, which took the written language further
from the intonations of speech. That's the system that shows up in most of the
early editions of her novels, and that's more or less the one we use today.

But who supplied the punctuation in the novels? Was it Austen herself, or her
publisher John Murray, or some nameless editor or compositor? Nobody knows. And
if we were talking about almost any other writer, nobody would care, either.
Fitzgerald or Hemingway's literary luster wouldn't be tarnished if it
transpired that their punctuation had been revised by an editor, although maybe
Kerouac's would. But when people talk about Austen's style, they're thinking of
those shapely clauses making their measured way from one semicolon to the next.
And if it turns out that the semicolons were actually put there by somebody
else, is it right to say that the style is hers?

Truth to tell, that's an embarrassing question. It reveals a certain obtuseness
- about writers and style, and not the least, about the semicolon. People have
the idea that mastering the semicolon is the acme of prose artistry, as if the
mark itself could call a logical structure into being. But semicolons don't
create a structure; they just point to one. It's nice to know where a semicolon
is supposed to go, but it's nothing to swell your chest over. The artistry is
in being able to write sentences that require one.

What's remarkable about Austen is the way that artistry shows up even in those
ragged manuscripts. The punctuation may look slapdash or peculiar to modern
eyes, but those complex sentence structures are always already there. You can
re-punctuate them according to the modern system without changing a word of the
text, rearranging the commas and dashes and dropping in a semicolon whenever
you come to an appropriate seam in the writing. You think of those masons of
old who could cut stone blocks so cleanly and precisely that they fit together
perfectly. Once the blocks were placed, it didn't really matter who came by
afterward to finish them off with a trowel.

GROSS: Geoff Nunberg is a linguist who teaches at the School of Information at
the University of California at Berkeley.

You can find a link to a collection of Jane Austen's original manuscripts on
our website, freshair.npr.org.

I'm Terry Gross.
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