History with David Rubenstein

(theme music plays) RUBENSTEIN: Hello, I'm David Rubenstein.

I'm gonna be in conversation today with Sidd Mukherjee, who is a Pulitzer Prize winning author.

He's also a physician, an oncologist, and a world-renowned commentator on health-related issues, I think it's fair to say.

He is, uh, also the author of a new book, The Song of the Cell, which follows his best sellers on the gene and cancer, and we're coming to you today from the New York Historical Society, the Robert H. Smith auditorium.

So Sidd, thank you very much for doing this.

MUKHERJEE: And thank you very much for doing this.

RUBENSTEIN: Okay, so let's talk about your background, before we go into this book.

And actually, I'd like to talk about your other books, as well.

But, um, where are you from?

Where were you born?

MUKHERJEE: So I was born in Delhi, New Delhi, India, in 1970.

RUBENSTEIN: And how did you wind up coming to the United States?

You went to college here?

MUKHERJEE: I went to Stanford in 1989, that's when I came.

I was 18 years old.

RUBENSTEIN: You turned down Harvard.

MUKHERJEE: Um, I did.

Uh, um, uh, it was a somewhat funny story about it.

They, the, um, I was accepted, and this was a time when there were four students from India, or five, who were accepted, to either Stanford, Harvard, whatever, and so, um, I got a book, a booklet, and, by mail, showing how beautiful Harvard Square was in 12 inches of snow.

Um, and I took a look at that, and it looked to me like a horror show.

Um, and I said, "There is no chance that I'm ever going to be there," except eventually, I would spend 14 years there.

RUBENSTEIN: Where'd you go to medical school?

MUKHERJEE: I went to medical school at Harvard into, back into the snow, out of the frying pan, or out of the cooling pan, into the freezer.

RUBENSTEIN: And you were trained as a oncologist, or... MUKHERJEE: So yeah, so I did internal medicine, which is the standard thing that you do, and then I, and then I did a fellowship in oncology.

There was a brief time, for about two or three months, when I had no job, when I actually helped run the emergency room, um, uh, as a kinda moonlighting gig.

RUBENSTEIN: And now you are at Columbia?

MUKHERJEE: And now I'm at Columbia.

RUBENSTEIN: Okay.

So let's talk about your first book, which won the Pulitzer Prize.

Uh, cancer has been around forever, I guess, right?

That's what you described in your book.

Uh, when did people first give it the name cancer, and what does the word cancer mean?

MUKHERJEE: So the word cancer is a, it's a strange word, it actually comes from, from Karkinos, or, or Greek for crab.

Um, we don't exactly know, um, th, there are two sort of competing theories about why it was called cancer.

One is that the, that the, the tumors, uh, with their blood vessels around them, uh, look like crabs under the sand.

Um, and then there's another theory that, that there's something about the, um, the shifting kind of quality of it, um, that reminded them of, of, of crabs a, again.

But that's how the name stuck.

RUBENSTEIN: So back in ancient Greek times, they, they had cancer then, people described it?

MUKHERJEE: Absolutely.

I mean, you can read books, um, you know, even Egyptian books, Egy, Egyptian scrolls, and I have a copy of one of them in, in the first book, where there's, there's a, there's a case description that sounds very much like breast cancer.

RUBENSTEIN: So it seems as if, that we've had a war on cancer, President Nixon announced a war on cancer, I guess, in the late '60s, early '70s, have we really made progress in reducing cancer, or eliminating cancer?

MUKHERJEE: So certainly not eliminating cancer.

So it really goes cancer by cancer.

And that's, uh, that's been the big mystery, um, for a long time.

But, uh, the answer is absolutely, yes.

Um, so the major risk reduction, um, was by reduction of smoking.

Um, so there was a peak, um, and it's come right down, so lung cancer, um, uh, cancer of the head and neck, um, cancer of the esophagus.

So that was a major, major move but I will tell you one, one thing that's important: this, it's not only true for, for smoking.

People say, "Well, okay, we stopped smoking."

You know, um, "M, most of us have changed our habits and behaviors."

If you take a disease like breast cancer, interesting, um, example, um, there has been about a 1% reduction in mortality in the United States from breast cancer for the last 24 odd years.

And every year, it seems minor, 1% comes to nothing, but the cumulative, uh, over 25 years has been a 25% reduction in mortality from breast cancer.

RUBENSTEIN: So if you have breast cancer, and discover it in, in first, stage one, you have a 97, 98% survival rate?

MUKHERJEE: Correct.

RUBENSTEIN: The most deadly cancers, they're all deadly, I guess, but the ones where the survival rate is, let's say, less than, uh, three or 4%, those are, um, glioblastomas, pancreatic cancer, liver cancer.

They're the three most deadly ones?

MUKHERJEE: Um, I could keep... RUBENSTEIN: You'd give more.

MUKHERJEE: On this nasty list, uh... RUBENSTEIN: Okay.

MUKHERJEE: For a while, but yes.

Those are among the m, among the most deadly ones.

RUBENSTEIN: And have we made progress on any of these kind of cancers?

They're just so hard to detect, because you don't see them until stage four, is that the problem?

MUKHERJEE: That's one problem.

Um, the second problem is that no therapy seems to have worked.

So glioblastomas a very particular, different example.

Glioblastomas kill you because they occupy your brain, um, and there's nowhere else to go.

Um, they don't kill you because they met, they, they metastasize.

They metastasize internally, inside the brain, but they don't metastasize to your lung, for instance.

Um, the other cancers, the main reason for the deaths of from these other cancers, pancreatic, colorectal and others, is because they metastasize, they move around in the body and they go to other vital organs and, and, and take up shop there.

RUBENSTEIN: So for somebody that is neurotic about getting some disease or something, would you say the best thing to do is not do anything, and not smoke, not drink, not eat, do anything?

I mean, what's the best way to avoid getting cancer?

MUKHERJEE: Well, the, I mean, the, he, here's the problem, and th, I'm going to make a very provocative statement, but it's an important statement to u, to understand.

Um, the provocative statement is th, is the following: um, since the 1970s, um, we have not discovered, and I'm gonna choose every word carefully, we have not discovered a major preventable chemical carcinogen of major impact on humans.

So I wanna say that again: since the 1970s, we have not discovered a major preventable chemical carcinogen that has large impact on human societies.

We've discovered many.

I'll give you one example: asbestos.

But... how many people are exposed here to asbestos?

Very few.

Beryllium, right?

Um, smoking was the last one.

The most recent one, and it's a question whether you wanna call it a major preventable chemical carcinogen, is the state of obesity.

So obesity clearly linked with many cancers.

Um, that's the most recent one.

So if you come and ask me, "What should I do?"

And, "Should I eat goji berries?"

Um, to, you know, "I'm so neurotic, I'd l, I'd rather eat goji berries for breakfast, lunch, and dinner."

I would say I, I, I don't know.

Now, that may be because we are not looking in the right place, uh, we haven't found the tools to look in the right place for these major preventable chemical carcinogens, or it may be that they don't exist, and, and the only com, you know, it's what I call the death by a thousand cuts theory.

Um, so that, you know, this is a big, big question in, in prevention.

RUBENSTEIN: In cancer, there are, are, like, three possible ways you get it: one is inherited... MUKHERJEE: Uh-huh.

RUBENSTEIN: It's genetic, uh the other is behavioral... MUKHERJEE: Yep.

RUBENSTEIN: And three is environmental, some exposure to something, asbestos.

MUKHERJEE: Well, I would say four is random.

RUBENSTEIN: Random.

Okay.

MUKHERJEE: Um, so that doesn't make the neuro, the, the neurotic in you happy.

RUBENSTEIN: Right, okay.

MUKHERJEE: And the... RUBENSTEIN: Uh, what about... MUKHERJEE: And the fifth is, is v, is viruses.

RUBENSTEIN: Okay, viruses.

Okay, so genetic, um, there are people now who get genetic tests, uh, 23 and Me and so forth, and they can say they have a, a certain predisposition to, uh, uh, a gene that has, let's say, cancer, breast cancer, something.

Do they make you crazier when you get these, or do you get calmer, that you know you have this and you have to do something about it?

MUKHERJEE: Well, it depends on the person.

Um, usually, um, it depends on your family history, it depends on, on how you approach the tests.

These tests are easy to deploy, but hard to interpret... you can have a BRCA1 gene and not get cancer.

Um, although, certainly, you have abo, about a eight fold risk above the general population.

But you could have a gene and not get cancer.

So you, you then need to make a decision whether you wanna live in the shadow of that knowledge for the rest of your life, um, or you wanna speak to a genetic counselor, or what you wanna do.

It just, it's a very personal decision.

RUBENSTEIN: So, for cancer treatment, the, the most common treatment seems to be the same thing we've been doing for 50 years, which is chemo and radiation.

Now, obviously, there's other things, we have some new ones, we'll talk about that.

But chemo was discovered when, as a, as a, possible way... MUKHERJEE: '50s, '40s/'50s.

RUBENSTEIN: Okay.

And radiation?

MUKHERJEE: Uh, '30s/'40s.

RUBENSTEIN: And those are still the most common treatments... MUKHERJEE: The most common, although, as I said, paradigms are shifting rapidly, um, in fact, for many cancers, even treatable, curable ones like, some leukemias, um, we're trying to actually back down from chemo.

The question is not how much chemo to give, but how little chemo we can possibly give.

Um, chemo is just really chemical therapy, right?

And the problem with chemotherapy is that it just, it's indiscriminate; it doesn't discriminate between a normal cell and a cancer cell, it just discriminates between a rapidly, or at least a dividing cell and a non-dividing cell.

So it's a, it's an unfortunate leftover, um, but, but certainly, again, take it, an example, breast cancer, we're using all sorts of modalities: hormonal treatment, immunological treatment, other kinds of therapies.

RUBENSTEIN: Let's talk about your second book, uh, which is The Gene.

MUKHERJEE: Uh-huh.

RUBENSTEIN: Um, everybody's, knows that they have the same, they have genes that are, uh, came from your parents, so when did we finally realize, that genes are the determinate of what we're gonna be like?

When, when was that really discovered, that genes are... Who discovered genes?

MUKHERJEE: So, um, it was, I mean, the idea of the gene, although he didn't name it, didn't even understand it, didn't even have an, have a proper, uh, didn't have a degree, for that matter, uh, failed all his exams, was Gregor Mendel.

Um, Mendel was a monk and he, um, in his monastery in Moravia, began to breed peas, and discovered that there were inherited traits.

What's important about Mendel is that he discovered that the, that these inherited traits were, um, behaved as if they were units.

Before that, people thought that, you know, that, that inheritance was like being inside a blender.

So everything, you know, your, your mother's traits and your father's traits, uh, got put into a, a benign kind of, um, medical or genetic blender, and you came out of the blender, and you get a mixture of both of them, and that's why you were, you, you know, you look like you do.

But, but Mendel was the first person to realize that it's not a blender, that if you look inside, that, that, in fact, they're pixelated.

Right, it's like looking at pixels.

RUBENSTEIN: Okay, so in the modern times, let's say, the last 50, 60, 70 years or so, uh, DNA has been discovered as the, the, the shape of DNA, double helix, was that one of the great advances in learning more about genes, when we learned what the shape was?

MUKHERJEE: A big advance came from just down the road here, from the Rockefeller, um, University, which actually, was a powerhouse, and continues to be a powerhouse of, uh, of, of basic scientific research.

Um, um, and that was Oswald Avery.

Avery was an, was kind of a shy old guy, and he was the first person to make the discovery that genes were carried in DNA.

People thought DNA was sort of stuffing, um, in the cell.

And so, that was really what set things off, Avery's discovery.

And then, of course, Watson Crick, Rosalind Franklin, Morris Wilk, Wilkins, saw the structure and they found the double helix and on and on... RUBENSTEIN: Now, about 20 years ago, um, two competing teams discovered the human genome.

Um, has that really helped us, when we have the human genome, we've mapped the human genome, and has that really helped us as much as we once thought it would?

MUKHERJEE: Um, I think that the reaction, from the standpoint of cancer biology, the reaction's been, uh, sobering.

Uh, I think the human genome is the, as all, as, I mean, I'm going to say a clich, is, is the, the end of the beginning.

Um, it is, we have just started being to a, able to utilize that information.

For 10 years, we didn't exactly what to do with it; we had this information, it was a template, but we've just started to use it, at least in medical and biological research, and we talked a little bit about how new tools, including CRISPR and other things have made the genome actionable.

It wasn't actionable before.

So there're various ways in which, now, in medicine, we are making the genome actionable.

It wasn't actionable, really, for about 10 odd years.

RUBENSTEIN: When did people realize that all of life is dependent on one cell or cells?

When was that discovered?

MUKHERJEE: Very late, and that's what's interesting about it.

Life is not DNA; uh, DNA is a molecule.

To become life, it has to b, it has to be inside a cell.

A cell, essentially, you can think of DNA as a score.

Uh, th, a cell brings it to life, it enlivens it, it reads the score.

Hence, The Song of the Cell.

Um, unless someone plays out that song, there is no life.

Um, but people didn't know this.

We, people, for the longest time, thought, into 1700s, we were made of slabs of flesh, and these slabs of flesh were continuous slab.

Um, and it was people, and it was, you know, actually two scientists, um, very different from each other.

Leeuwenhoek, um, who, who made a microscope.

Looked down in tissues, and looked down in water, and found single celled organisms floating in the water.

And, um, Robert Hook, a great polymath, um, completely different, uh, at Oxford, um, and then finally, the Royal Society, looked down his microscope and saw that in plants, there were cells.

And there's another, like Mendel, there's another period of about 50 years when nothing happens.

And then the book opens with two, uh, zoologists and a botanist, Schleiden and Schwann, making the realization one evening over dinner in Berlin, that all animals and plants share this common feature, that, that, that they're all made out of cells.

RUBENSTEIN: So when was the first cell on the planet Earth?

MUKHERJEE: There's a good estimate, uh, probably around 3 billion years ago.

RUBENSTEIN: So you have the first cell, and is it your theory, or other people's theory, that the first cell then became multiple cells, and ultimately, ultimately, all life came from that?

Or were there, simultaneously, single cells that ultimately became different animals or species?

MUKHERJEE: Most biologists, uh, think that the, that our lineages, if you wound back the, uh, the, the, the, if you wound back time, would end up with that one cell.

And that's called the, uh, last common universal ancestors, or sometimes called LUCA.

RUBENSTEIN: So what caused that first cell, and other cells now, to divide?

Why, why does a cell divide?

Why not just sit there and just wait for something to happen?

MUKHERJEE: Well, because if cells didn't divide, nothing would happen.

RUBENSTEIN: Right.

But what causes a cell to divide?

MUKHERJEE: So you need some information carrier, because the next cell needs information.

A division of a cell is essentially division of information.

So you need an information carrier, which is sometimes called a template.

You need a duplicator, um, uh, to make a copy of the template, and then you need a splitting mechanism.

Um, and you need to confine, the splitting mechanism needs to be confined, otherwise these chemicals would float away, and you would never have a di, a second cell.

RUBENSTEIN: So when cells divide, the theory is that they divide in an appropriate way, without a pathogen or some, um, defective cell, but what causes some cells to divide in a, in a way that creates a disease?

MUKHERJEE: Well, I mean, cancer's a good example.

I mean, you know, when this, when cells divide, uh, they can accumulate mutations, so you, they can make errors in their copying of their genes; that's one way that you can get a disease in which a cell doesn't stop dividing.

I mean, when you cut yourself.

Why don't you grow a new hand?"

Um, and the answer is, we don't know.

Um, we know a little bit about it, but somehow or the other, when you cut yourself, your skin cells divide and divide and divide to heal the cut, and then, when they touch each other, they know when to stop dividing.

Otherwise, you'd become a tree.

You'd, every time you cut yourself, you'd have a, a new limb growing of your b, body.

Um, so, so there are processes, like brakes and accelerators in a car, that promote cell division, and tha, that stop cell division.

We know some of these processes; we don't know all of them.

We know some of them.

In cancer, that process goes wrong.

RUBENSTEIN: So talk about the reproduction.

So how is it that reproduction works?

A, a sperm cell goes to an egg cell, and all of a sudden, you have an embryonic cell?

MUKHERJEE: Uh, a zygote, yeah.

So, um, and so, interesting: sperm cell, smallest cell in the body, egg's the largest cell in the body.

There's a reason for that.

Um... RUBENSTEIN: What, what is it?

MUKHERJEE: A sperm is just a mechanism, it's just a, a, it's a piece of DNA that's been tightly coiled up and wound up, just to throw it at, at, at an egg.

That's all it's doing.

It's just carrying...

It's a, it's a DNA carrier, fancy DNA carrier with a tail.

RUBENSTEIN: All right.

MUKHERJEE: Uh, the egg cell is very, very different, because the egg cell has to contain, uh, and, and I, th, and th, the, um, very seriously, the egg cell has to contain a lot of spatial information.

It has to know what's up, what's down, what's left, what's right, what's front, what's back.

'Cause once the sperm has entered the egg cell and formed a zygote, that polarity of the egg cell, the information that is deposited in the egg cell, in different parts and phases, and different, is the information that's gonna make it unfold into an embryo.

RUBENSTEIN: Okay let's talk about the, the heart.

The heart, uh, when was it discovered that the heart really is a unique part that really is the, the furnace, in effect, what you say, for the, for the body, it, it moves the, the, the blood around, uh, what is it that propels the, the, the heart cells to actually pump?

MUKHERJEE: Well, the history is very interesting.

I mean, you know, this, it, it goes back, um, to work performed by William Harvey, again, very important historical work.

Harvey was an, um, uh, a physiologist and experimentalist And for the longest time, and historically, people believed that the heart was a warming furnace, and that, really, the only function was, it was a, you know, it would, would keep the, the, a pump that would be the heating oil of the body.

Um, and blood was the, uh, was the heating oil.

Um, but, um, Harvey performed extraordinarily simple experiments, um, historical experiments, in which he would just, b, by using just simple things like tourniquets and, you know, um, stopping the blood, bleeding animals, et cetera, et cetera, he figured out that the heart was a pump.

And, in fact, he figured out the heart was two pumps: one pump was a circuit between the heart and the lung, which gives it oxygen, and the second pump is the pump that then takes that oxygenated blood and pushes it to the rest of the body, where it goes and delivers oxygen and nutrients and other things.

RUBENSTEIN: You point out in your book, uh, that, when somebody gets a cut, uh, platelets rush to kinda preserve the skin, and keep the body from being damaged.

The same thing happens with the heart, but when the platelets go into the heart, they have the opposite effect of what you really want.

You don't want something that is then gonna coagulate so much, because it's... Can you explain why we didn't have heart attacks 1,000 years ago as much as we have them now, and ho, why we have to have blood thinners to kind of deal with the heart problem?

MUKHERJEE: Well, this is the strange thing about human history and behavior, is that as environments changed, as behaviors changed, as human beings changed, as diets changed, as our habits changed, what was once physiological becomes pathological, and what's pathological becomes physiological.

So the, the physiology was invented, obviously, not to cause heart attacks, but the common problem was wounds.

And especially, um, there's one moment in, in human biology where it's extraordinarily crucial that blood clots, and that's childbirth.

This is a major cause of mortality way back when.

Now, unfortunately, physiology has changed into pathology in the current era, where the major problem is no longer bleeding, it's clotting.

And so, um, and it's clotting in arteries like the heart, and so what was once invented evolutionarily as a mechanism to conserve your body, has become a mechanism to kill you.

RUBENSTEIN: So let's talk about another type of cell: neurons, brain cells.

So how are they distinctive from the other cells in the body?

MUKHERJEE: Well, brain cells have a completely different physiology.

Um, because their job is to, um, act as conduits of, of, uh, impulses.

Um, and the, for a long time, again, going back to history, for a long time, people didn't know, um, whether brain cells, you know, how they were, how this was all connected.

And it was actually, um, an artist, uh, um, Santiago Ramn y Cajal, there's a very beautiful picture of his, um, in a, of one of his drawings in the book, who figured out that, in fact, these neurons, these nerve cells, number one, that they were cells, people didn't even know that they were cells, people thought they were some kinda wiring, uh, that they were cells, and very importantly, in Cajal's drawings, he figured out that brain, the neurons don't, uh, are not a continuous network.

They have interruptions between them.

Um, and so the signal that goes in the neurons is electrical to the neuron, then changes to a chemical signal, then changes back to an electrical signal, and then to a chemical signal.

So it's chemical, electrical, chemical, electrical, chemical, electrical down the entire nervous system.

RUBENSTEIN: Okay.

So let's talk about something you write about in both of your books on, on cells and on genes, which is the CRISPR phenomenon.

So if somebody wants to have blue eyes as opposed to brown eyes, you can maybe do that.

Can you describe what CRISPR is?

And then we'll talk about what happened in China.

MUKHERJEE: Yeah, so CRISPR is a bacterial enzyme.

It's, um, and that was discovered by, um, discovered by a huge team, very esteemed, of scientists, but ultimately, put into, um, sort of scientific practice by Jennifer Doudna and Emmanuelle Charpentier, who won the Nobel Prize for it.

MUKHERJEE: So, um, CRISPR is a system that can make directed changes in DNA.

Our genomes are 3 billion, um, base pairs: A, C, G, T, T, G, C, A, A, C, G, T, D... Whatever it might be.

RUBENSTEIN: Right.

MUKHERJEE: Um, CRISPR has the capacity, uh, if you give it a guide, an RNA molecule, to go into that genome of 3 billion base, uh, bases, and make a directed cut, um, and potentially, using other technology, make a directed change, um, in one place in that 3 billion, uh, uh, odd genome.

So that's the technology.

RUBENSTEIN: So the concern that some people have had is, we might be able to create humans that are different than our genes would otherwise want us to be.

And so, in China, one doctor, uh, who just, I guess, served time in jail for doing this, what did he do that was so outrageous to the medical profession?

MUKHERJEE: So, just to answer your first question first, um, which is, "Can you make blue eyes, and can you make," um, um, whatever else you want, t, taller people, the answer is very difficult with CRISPR, because most, traits that we have as humans, the color of our eyes, our hair, our height, et cetera, are governed, not by one gene, but by hundreds, if not thousands of genes.

RUBENSTEIN: Right.

MUKHERJEE: And that's a very important discovery.

So virtually every trait that we inherit, uh, is polygenic, um, multiple genes are involved.

And making CRISPR make 50, 60, 80, 100, 200 cuts, and changing that information would be extraordinarily difficult.

Now, coming back to the Chinese, uh, case, a scientist named He Jiankui, um, f, um, there is one gene that acts as a co-receptor for HIV.

Um, it's a gene, so the main receptor for HIV's been long identified, but it's a gene called CCR5.

And he decided that he was gonna edit using CRISPR.

He was gonna edit that in, uh, some babies.

RUBENSTEIN: So the babies would not get HIV, theoretically?

MUKHERJEE: Uh, theoretically.

The problem was that he recruited patients where the father was HIV positive, but the mother was HIV negative.

So these babies had no risk of getting HIV anyway, because their risk was zero.

Um, this is where the problem began.

There are many other problems.

There was a lack... RUBENSTEIN: Consent.

MUKHERJEE: Of informed consent, there was a la, there was a lack of, um, understanding.

So in fact, the, you know, whenever you make such a bold, uh, clinical experiment, you have to convince yourself, and if you can convince the scientific community that the risks outweigh the, the, the benefits.

The benefits could have been, you know, they, we still don't know, um, what the potential benefits could have been.

RUBENSTEIN: These babies were born.

MUKHERJEE: And these babies were born, a, twins.

Um, and unfortunately, we know very little about them, because no, no scientific magazine has yet... is yet to publish the real data on these twins.

RUBENSTEIN: Can you see 10 years, 20 years from now, people being able to design their babies a little bit, maybe not with blue eyes, but they won't have a predisposition to Alzheimer's, or, or breast cancer, or prostate cancer?

MUKHERJEE: So when, only if there are genes, and there're a few in the genome, um, where, um, there's a single gene which is highly likely to, so the, the, the link between the gene and the disease is very direct and strong.

Um, even then, there are alternatives.

So for instance, biopsying cells, and choosing not to implant, um, babies which I, or zygotes, um, that happen to have the, the, the gene.

That's, uh, called prenatal genetic diagnosis, and is now available.

You can use it to prevent, for instance, um, uh, if you desire not to have a child with a particular genetic endowment, you could choose to do that.

You don't need CRISPR to do that.

RUBENSTEIN: Well, look, uh, this has been a great conversation, and I wish we had more time, but I hope we gave people a sense of, uh, of your, um, incredible skills of writing and narrating, and also your medical skills.

So thank you very much for this book, and the other two you've written, and I look forward to reading the next one.

MUKHERJEE: Thank you, David.

Thank you.

(applause) (music plays through credits)