Siddhartha Mukherjee on Getting Personal with Our Genes

Siddhartha Mukherjee
I’m Alan Alda and this is C+V, conversations about connecting and communicating.
Siddhartha:Just this to be very clear, there are many dangers of CRISPR, but in the history of human beings, in the history of humankind, we have not come across a molecular machine with this level of ease, that can allow us to alter genomes. It is a powerful tool. It can be misused, but let’s not underestimate the enormous good use that CRISPR can be put to.
That’s Dr Siddartha Mukherjee, talking about the extraordinary power scientists like him have now to edit our genes using the tool known as CRISPR. Dr. Mukherjee uses CRISPR in his own laboratory at Columbia University here in New York to pioneer innovative ways to treat cancer. And, he’s masterful storyteller. He’s the author of the best-selling, Pulitzer-prize-winning book, “The Emperor of All Maladies: A Biography of Cancer.”
I think what makes him so readable, apart from his obvious command of the science behind his books, is his ability to make it all personal and intimate.
We talked about that when he sat down with me in our studio in New York.

Alan: 00:00 This is so great that you could talk with me today what’s wonderful I think is what a good writer you are about your work and about the whole field. Your latest book, The Gene: An Intimate History, is an intimate history. Your stories about your uncles and your cousin who suffered from schizophrenia. Did you do that deliberately to make the material available to us?
Siddhartha: 00:58 No, right from the very beginning… Well, first of all, thank you for that nice introduction. Right from the very beginning I’ve thought about the process of writing about anything in science as intimate. That is-
Alan: 01:17 That’s interesting. What do you mean by that?
Siddhartha: 01:18 That means that there’s a false impression, at least a false impression to me, if you’re not embedded in the sciences, particularly if you’re not embedded in medicine. There’s a false impression that things happen outside in some kind of abstract space. But that’s obviously not true. Medicine comes into your life as the moment medicine, medical science, science enters your life, you are transformed and you are being touched by it constantly. There is an intimacy to the life sciences, which is what I mostly write about. That’s necessary. It’s part of you. The minute you cross the border between being well and being ill, the minute your friend does, the minute your son does, your daughter does, your parents do, you all of a sudden experience the intimacy of medicine, the intimacy of biology.
Right from the beginning when I started writing, I thought to myself, I made a rule and I actually follow that rule. The rule is basically that you won’t go through six pages of my book without encountering a real character. Someone real-
Alan: 02:32 Oh, that’s great. You made that a rule.
Siddhartha: 02:32 I made that a rule.
Alan: 02:34 That’s great.
Siddhartha: 02:35 The rule is that you cannot go beyond six… That character might be me sitting in the lab one evening thinking about something. That character might be my cousin suffering from schizophrenia in an institution in Calcutta. It might be a scientist whose life you didn’t really know about. But you never traverse six pages in the book without suddenly realizing this could be you. This could be someone you knew. This is part of who you are. This is part of your life. It’s not outside you. This is not some white coat thing that’s happening.
Alan: 03:11 I get the impression that it’s not just a writing technique, but, from reading what you wrote, it sounds like that’s the way you conduct your research as well. I don’t get the impression you studied the mechanics of genes and the rest of biology as something apart from us. You seem to be always thinking about the effect it has on us as people.
Siddhartha: 03:35 I also made that a rule in my laboratory. I actually made that after I began to write. The unspoken rule in my laboratory is that, unless you can justify what you’re doing as having a human consequence, a consequence for a human disease, that project is not for our laboratory. Now, I have to clarify something very important here, which is that my lab and other labs are enormous beneficiaries of basic research. Things that come from the microbial world, bacterial world, CRISPR, enzymes that we borrow from the bacterial world, techniques, are vastly important to us. But my identity, the skillset that I bring to the table is a translational researcher, someone who can translate between basic sciences, and the insights of the basic sciences, into human medicines.
My laboratory occupies a intermediary zone, a zone in the middle, and that’s the strength of the lab. About four or five years ago I thought to myself, if that’s what I’m naturally the most interested in, I’m naturally more interested in making medicines. I like making medicines. I like making therapies, obviously for human beings, not for mice.
Alan: 05:09 You’ve probably cured a lot of mice along the way.
Siddhartha: 05:12 Yeah, I’ve cured a lot of mice along the way, but I like making therapies for human beings, and I’d like to see them come alive as medicines.
Alan: 05:18 What do you do if you start to bump up against something that if you pursue it a little more, could bring us a deeper understanding of basic science? Do you pursue it or do you say, “Let’s just get on with the other one?”
Siddhartha: 05:31 I have a very clear strategy. When I come up and I bump up against that, I try to find the best collaborator that I can in the field who works on that problem. I call that person up and I say, “Would you like to help me solve this problem?” It works every time. I can give you a hundred examples. Every time we’ve bumped up against problem like this, we’ve sought out a collaborator and said, “Can you help us work through this? You’re a basic scientist. I’m more of a translational scientist. I need this piece from you,” and we collaborate. I’ve never had an acrimonious collaboration.
I think the reason that lots of people who think that, it’s science, it’s complicated to collaborate because you never get, sometimes you don’t get the credit you need, et cetera, et cetera. Sometimes you have a dispute with the other scientist. I’ve never in my lifetime had an acrimonious collaboration, and that’s because for two reasons. Number one is that our roles are quite well defined. As I said, what gets me moving in life is making human medicines. I like making medicines. Someone else might say, “What gets me in life is understanding nature. I’m driven by curiosity,” and those are yin and yang phenomenon, so they work very well.
The other reason is that when you tell someone that you’re doing something to emancipate some form of suffering, some disease, the problems that you have in the laboratory, which postdocs said what, and which researcher deserves credit. All of those melt away given the magnitude of what you’re trying to accomplish. I’ve never had an acrimonious collaboration and that’s what happens. I seek out collaborators.
Alan: 07:21 When I think of how personally you made, especially the opening paragraphs of your book, get right down to the presentation of a character that the reader can suffer along with. It reminded me of my own mother who suffered from schizophrenia and paranoia most of her life.
Siddhartha: 07:21 I did not know that.
Alan: 07:43 I was of course drawn to your story, but I think everyone will be because it’s so human. It made me wonder, living with illness like that, did that in some way motivate you to want to devote yourself to medicine rather than, as you said, rather than the big secrets in nature?
Siddhartha: 08:08 I came into medicine a little bit backwards. Very unusually, I think. I was an undergraduate. I worked in a lab. I worked in Paul Berg’s lab. Paul Berg and I are still friends, I actually got an email from him yesterday. Paul Berg discovered and won the Nobel Prize for discovering the technology that allows us to combine genes to make hybrid or chimeric genes. Take one gene from a virus and one gene from a bacteria and mix and match them together, stitch them together into a single unit, and all of a sudden nature reads it as if it was one gene. That requires technology. It requires cutting and pasting technology. The field is called recombinant DNA. Paul invented recombinant DNA. I worked with Paul and I thought at that time that I would be a basic researcher. This was when I was in my twenties.
Alan: 09:11 You started out there?
Siddhartha: 09:12 I started out there. Yes. Then I went to Oxford to do my PhD, which is, again, backwards. Usually people do half of their medicine degree first, and then a little bit of the PhD, finish their PhD, and then come back to medicine. Mine was totally backwards. I went to Oxford and I started studying a virus called Epstein-Barr virus. It’s a very common virus. Most of us have it. We carry it chronically.
The question was a question that started off as a basic question, which is, why is it that if you get the flu, influenza, your immune system completely clears the virus and you can’t find the virus in your body once you’re done with the flu. But with Epstein-Barr virus, how can this virus live inside your body forever? You still have a competent immune system. Why is it that the flu gets eliminated, but Epstein-Barr virus doesn’t get eliminated? It turns out that there’s a series of very basic problems that you have to solve to figure out why that happens. Why Epstein-Barr virus, or herpes virus, or chicken pox virus, a great example.
Alan: 10:19 All these things that linger.
Siddhartha: 10:21 That linger often in this [crosstalk 00:10:24]-
Alan: 10:24 [inaudible 00:10:24].
Siddhartha: 10:26 Yeah, that’s sort of virus. But yeah, things that linger and can be reactivated, they lie dormant within you. Why that? So that started off as a basic science problem, but then I became interested in the fact that this virus is not just a machine. Actually, it causes disease, it causes illness, and one of the illnesses it causes is cancer, so I became interested in cancer. The latter half of my graduate work I started working on cancer. Then I thought to myself, “Gosh, this is more interesting to me than solving those molecular clockwork puzzles which were also fascinating,” and I said… Also other people are better at it than I am, solving those molecular clockwork puzzles.
My skill set is more of someone like an inventor. I like to invent things. I like to take those pieces of clockwork and say, “How can I now jigger it a little bit differently and make a medicine out of it?” That’s what I like to do. I like making medicines. I like making therapies, obviously for human beings, not for mice.
Alan: 05:09 You’ve probably cured a lot of mice along the way.
Siddhartha: 05:12 Yeah, I’ve cured a lot of mice along the way, but I like making therapies for human beings, and I’d like to see them come alive as medicines. It’s not always achievable. This is a tough nut to crack as you very well know, but that’s what was more interesting to me, so I thought, “Why not do that?” That’s how I came to it.

MUSIC BRIDGE
Alan: 11:44 It sounds like you were able, as you were putting all these things together that were already known, you had to also keep up with what was increasingly known. It seems like the knowledge has been growing at a rapid pace. The idea that… I mean, it’s an old idea, I think, that goes back to the Fly Room-
Siddhartha: 12:05 That’s right, at Columbia-
Alan: 12:06 … at Columbia where they were working on fruit flies and got some basic understanding, but then since that’s like almost, or more, than 100 years ago and it’s rapidly increasing. What did they find out in the Fly Room?
Siddhartha: 12:19 Well, gosh, the Fly Room is one of those places in the history of biology and medicine where discoveries came upon discoveries, came upon discoveries. It was like a spray of Nobel prizes came out of that Fly Room.
Alan: 12:19 Generation after generation of scientists-
Siddhartha: 12:33 Generation after generation of scientists, and that’s because they were studying an organism which reproduces very rapidly, and has mutations, and you can track those mutations. What came out of the Fly Room? Lots of things. Well, first of all, one thing that came out of the Fly Room is the idea that genes don’t sit like molecules, separated in space. They are linked together. They are tied together like beads on a string. That’s the phenomenon is called linkage. That phenomenon was discovered first in the Fly Room in fruit flies.
Alan: 13:08 In other words, to get a certain condition or attribute that a person has, it takes the collaboration often, of more than one gene?
Siddhartha: 13:18 That is a separate idea that also came out of the Fly Room.
Alan: 13:20 What’s the linkage?
Siddhartha: 13:22 The linkage is that the genes are physically linked together. That in fact, one gene sits next to each other on a chromosome like beads on a string. This was not known in the 1920s. People had all sorts of ideas about what the physical structure of a gene would look like.
Alan: 13:39 I remember in the book something, but is this related to what you’re talking about, that blonde hair and blue eyes often go together because the genes are right next to each other.
Siddhartha: 13:50 Yeah. That’s a fictional example, but there are other very nonfictional examples. There are diseases that often go together because their genes sit close to each other. There are traits that often go together because their genes are linked together. For instance, I’ll give you a classic example of one. One form of color blindness in humans is linked, it sits on the Y chromosome. It is male-linked, only men have it. You have example after example in which you have a physical trait that can be tracked back to a gene, but genes don’t live in space in isolation. They are linked to each other. They are physically, as I said, like beads on a string. That idea came out of the Fly Room.
Now that idea in turn is part the basis of the Human Genome Project. Years later it would be using these same kinds of tools that people would figure out which gene is linked to whom, and thereby be able to construct a linear map of genes. Once you’ve constructed a linear map of genes, that’s the first step towards the Human Genome Project, which is to completely map, in all chromosomes, all human genes.
Alan: 15:17 But once you map it, aren’t you stuck with the problem that it’s not just this gene causes that problem, but sometimes it’s a combination of genes that cause a problem, and the time or sequence in which they’re activated. Isn’t that a question too?
Siddhartha: 15:36 Both of those are incredibly important questions. Many of them also came out of the Fly Room by the way.
Alan: 15:41 Oh wow. What hope do you have with so many variables? How can you put these ideas together to connect the genetic sources of a disease with the disease itself?
Siddhartha: 15:56 The first thing one has to understand is that there are various kinds of diseases. There are some diseases in which basically one gene, or a mutation or a change in one gene, is enough to cause the disease. There are some diseases, if you inherit one copy of that mutated gene, you would inherit the disease or have the disease. A good example of this is Huntington’s disease. As far as we can tell, to the first approximation, if you were to inherit a mutated copy of the Huntington’s disease gene, you would, in your lifetime, have that lethal neurodegenerative disease. That’s a monogenic, single gene disease, and it’s a dominant.
Then there are diseases which are also monogenic where you need two copies of the gene in order to get the disease. You need one copy from your father, one copy from your mother, and when you have both the copies and both of them are mutant, you get the disease. These are simple diseases and unsurprisingly they were mapped first. These are diseases like sickle cell anemia, cystic fibrosis, and other diseases like that where, again, you have either one copy of the gene or, in these other two recent cases, two copies of the gene are enough to cause the disease.
On the far end of the spectrum, you have diseases such as schizophrenia, bipolar disorder, depression, which clearly carry a genetic link, but two things are true. Number one is that, generally speaking, no single gene explains the disease. It’s a combination of maybe hundreds, maybe several hundreds, maybe even a thousand odd genes that are required in order for you to get the disease. That’s one thing. The second thing is that these diseases are often, not always, but often triggered by either chance or by the environment. Cancer is an example of this as well. We can talk about that later.
If you think about that taxonomy of human disease, it is like the taxonomy of normal human traits. On one end you have things where one gene is necessary and sufficient to cause that trait or that disease to happen. I gave you some examples of that, but on the other end, and in fact this is the more common end, most common diseases, heart disease, coronary artery disease I should say to be more particular, schizophrenia, and other diseases have genetic links but one gene is not sufficient, and the environment, and chance, and triggers play a big role in unleashing the disease and making it become real as it were in a human being.
Alan: 18:47 This brings up a serious question in my mind and I’m really curious about what your thinking is on this. If you take a disease like schizophrenia, which we both know from personal experience is extremely painful, not only for the patient, but-
Siddhartha: 19:03 For the family-
Alan: 19:04 … for the family. It’s really, really difficult. If that disease has the interaction of 1000 genes, and in addition to that you don’t know in which order they’re expressed or at what time and how long it takes before the next one, that kind of thing. Now that we have the tools to really manipulate the genome, like CRISPR, where you can go in and cut out exactly what you want to get out and put in what you want to put in, are we not in danger of mucking it up because we don’t know what the unintended consequences are? We might fix one aspect of the problem and cause another serious one, which, unless I’m wrong, can be inherited by the children.
Siddhartha: 20:01 You’ve raised an enormous set of issues, and we should go through them systematically. Let’s take a step back first. Let us take a disease which is highly polygenic and influenced by the environment. It has a very strong environmental [crosstalk 00:20:24]-
Alan: 20:24 What would that be?
Siddhartha: 20:26 Coronary artery disease, what we commonly call heart attacks. We now know, and this is actually very recent data, that you can predict… before you could predict your risk of having coronary artery disease based on your age, based on your gender, based on whether you had high levels of LDL this low density… cholesterol basically.
Alan: 20:53 Does family history play a part-
Siddhartha: 20:54 Family history, exactly. Hypertension, a whole bunch of risk factors. But among those risk factors, absolutely was family history. As soon as you hear the word family history, you have to start thinking, ding, ding, ding, ding, ding genetics. We now know, from very elegant work done in Boston by Sekar Kathiresan who actually was one of my teachers as a resident. Very elegant work done by his laboratory, which shows that you can now predict to a great degree of accuracy, based on your genetics alone, whether you’re likely to have or suffer from coronary disease in the future or not. The number of genes is quite a lot. It’s not one gene, it’s not two genes, although there are certainly one or two genes that dominate. The number of genes is many for most people, not unusual rare syndromes. But for most people who have a risk of coronary disease, the number of genes is many.
You could say, well, should we be nihilist about this whole situation, because, I mean, what do we do? Well, you can actually [inaudible 00:22:02] for that disease. You can do many things. You can do early interventions. You can monitor people, you can put them on medicines that might lower the risk of heart attacks. Although the picture of highly polygenic disease sometimes makes you feel like a nihilist, it’s so complicated, how on earth could we solve this problem? There are certainly growing numbers of examples in which, despite the fact that there are many genes involved in a problem, the genes cannot be manipulated, but the physiology can be manipulated in a way that you can prevent the disease. That would be one non-nihilistic answer to what we could do.
The second answer, which you’re getting at, is could we use CRISPR? Could we use CRISPR to alter the genes? It would be an enormous technical challenge because CRISPR is very good right now. The tools that we have with CRISPR, and we use them extensively, I used them extensively in the laboratory. CRISPR is very good at single gene problems. CRISPR, right now, it’s not designed to take multiple genes and make multiple alterations in multiple genes for lots of technical reasons. It’s not designed to do that. It can be, one could imagine that you could use it serially as it were. Change one, change the other, change the third, or maybe change three at a time or four at a time, but it’s not designed to change hundreds of genes at the same time.
Alan: 23:35 First of all, you’d have to be pretty sure that you’re making changes that don’t interact with one another in an unfortunate way.
Siddhartha: 23:45 You absolutely have to do this. In fact, there are many examples in which this is, even with single genes that’s not true. The two effects that you need to watch out for if you were to do this in a human being, and if you were to do this in a human being in a way that would be inherited by their children, one is you’d have to make sure that you’ve actually changed the gene that you want to change, and not some other genes. That would be an off target effect off the technology. In other words, like a pair of scissors, rather than cutting the right gene, CRISPR went and also made a cut in some other essential gene. For the most part if-
Alan: 24:24 Let me just stop. That scared me a little bit. How probable is that?
Siddhartha: 24:32 It depends very much on how you design the machine. In some cases, in our case actually, we found that you can optimize the design of the machine such that you don’t get cuts in other places as far as we can tell. You have to be very careful, basically.
Alan: 24:51 Is the idea of CRISPR that you take over the mechanism of either a virus or a bacteria, I might forget which.
Siddhartha: 25:01 Right. CRISPR is a molecular machine. You should think of CRISPR as a set of… It’s a set of tools-
Alan: 25:10 The size of a molecule.
Siddhartha: 25:12 That’s right. The main active pieces of CRISPR as it were, the toolbox, is a particular molecule. Actually, it’s a collection of molecules. They come together. It’s a machine that can make deliberate cuts in DNA at a deliberate site, at a specified site.
Alan: 25:37 You give it the address, and it goes to that address.
Siddhartha: 25:40 That’s exactly right.
Alan: 25:42 How do you know it’s not 123 Houston Street or 123 A.
Siddhartha: 25:47 Exactly, CRISPR can make that mistake. That toolbox can make the mistake between 123 and 123 A Houston Street. The best example someone gave me recently is that, apparently there’s a Bible called The Wicked Bible in which they made a transcriptional error while the person was writing it. Rather than writing, “Thou shalt not commit adultery,” they missed the word not, and the Bible reads, “Thou shalt commit adultery.”
Alan: 26:16 This explains so much.
Siddhartha: 26:18 Exactly. The question you could be asking is-
Alan: 26:21 The next thing that happened were divorce lawyers.
Siddhartha: 26:24 Exactly. Exactly, and they have to be CRISPED out. But to go backwards, you’re exactly right. How do you know that it won’t go to one 123 A and deliver the parcel, which in this case, the parcel happens to be a bomb, a pair of scissors, right? It will cut the house.
Alan: 26:44 How do you guard against that? Does it just happen infrequently enough to not make it important?
Siddhartha: 26:49 It happens infrequently. It happens under particular circumstances. It happens when the addresses are very close. In other words, it happens when there are two genes that sound like 123 Houston Street and 123 A Houston Street. When you have two genes like this, chances of both being cut or being messed up become higher. Whereas if you have 123 Houston Street and 123 Boston Street, the chances of CRISPR figuring out the difference is quite high, because CRISPR doesn’t usually cut Boston, it’ll cut only Houston Street.
That’s one. That’s the off target effect of CRISPR as a technology. But you’re asking a second question, which is a deeper question, which is, so let’s suppose you actually cut the right address, you get the right address, you go to 123 Houston Street. How do you know that eliminating that house won’t all of a sudden cause every other house in the neighborhood to start toppling down because it turned out that there was a common wall between all of them.
Alan: 27:55 Is there, I’m imagining time issues too. Tell me if I’m too imaginative here.
Siddhartha: 28:01 There are time issues too-
Alan: 28:03 If you alter a gene that’s useful now to this person, but there’s something that you’ve done that skips a generation, you might not know that you’ve done harm until there’s a grandchild.
Siddhartha: 28:18 That’s correct. There could be a time issue. There could be environmental issues as well, I’ll give you very practical example-
Alan: 28:23 Or make somebody more susceptible to an impure environment.
Siddhartha: 28:28 That’s exactly right. There’s a very practical example which has already occurred, which is-
Alan: 28:31 What’s that?
Siddhartha: 28:32 Well, as you might know there was universal condemnation of the idea that a particular gene was altered in two Chinese girls. We know from other lines of evidence that these two genes may be involved in protection against a virus. The logic of the experiment was to protect these two girls from HIV because these genes are permissive factors that allow HIV to essentially enter and replicated inside cells. The problem was that these girls had no risk of HIV. Their father was infected and as you very well know, you don’t pass on HIV infection through sperm. It is a bloodborne infection. The risk of these children having HIV was basically nil.
Despite that, the scientist went ahead, obtained, what we think now is very shoddy consent, not very good consent, from the parents. Of course, the embryos could not give consent. Two children were born, two girls were born, with a genetically modified genome with a change that was, I should say, partly deliberate. We don’t know all the details because the case is under a lot of investigation. But what we do know is that gene, the gene that was affected, presumably to protect these kids from HIV infection, those genes are also involved in protecting people from infections by other viruses. The scientist may have set up these children actually for greater danger, and that’s one of the cardinal principles of medicine, first, do no harm. That’s one example of CRISPR gone wrong.
Just this to be very clear, let’s be very clear about it, there are many dangers of CRISPR, but in the history of human beings, in the history of humankind, we have not come across a molecular machine with this level of ease, that can allow us to alter genomes. It is a powerful tool. It can be misused, but let’s not underestimate the enormous good use that CRISPR can be put to.
When we come back after a short break Dr. Siddhartha Mukherjee tells me about how he is himself using CRISPR in a novel way to treat a cancer that up until now has been incurable.
MIDROLL
This is Clear and Vivid, and now back to my conversation with Dr Siddhartha Mukherjee.
Alan: 30:57 Right. I think I’ve succeeded in part in scaring people with my caution. In spite of my worries about it, I’m pleased to see that scientists around the world are talking cautiously about the new tools available like CRISPR and talking about the ethics of doing certain things. But one of the things I wonder about is, I don’t get the impression that, that’s organized. That everybody’s up to their own cultural and personal decision making process.
Siddhartha: 31:35 It’s certainly organized by nation, or in many nations I should say. In the United States we’ve now had several documents by national authorities giving scientists advice about what to do and what not to do with CRISPR. We are running actually one of the most exciting studies that I’ve ever done in my life with CRISPR.
Alan: 31:59 Tell me about that.
Siddhartha: 32:02 It’s an incredibly exciting study, and it’s in leukemia. It’s in a form of leukemia, blood cancer, white blood cell cancer, which is often insurable. In one particular subset of these patients, the mortality rate can be 98%. All of them die. For generations, people have tried to find things on the cancer that they can direct an immune attack against, that are not present on normal cells. The problem in this form of leukemia called acute myeloid leukemia, AML, is that we’ve never found such a thing. Every time we find something on the cancer cell, it’s also present on normal blood cells. You throw a bomb at the cancer-
Alan: 32:53 You kill a good cell.
Siddhartha: 32:54 … and you kill a good cell. The problem is that these good cells you can’t live without. These are your blood cells. These are cells that form. We were stuck in this kind of immunological impasse. We couldn’t fight the cancer even though there were many things on the cancer that were visible. But if you fought them you would kill a normal cell. Now, the study that we’re running is a kind of study in inverse, I call it a black and white study. Because what we do is we say, “Let’s not go after the cancer. Let’s leave the cancer cell alone. Let’s change the host cells. Let’s use CRISPR to take away something from the host cells-”
Alan: 33:36 Well, what’s a host cell? What do you mean?
Siddhartha: 33:39 Host cell means the normal cells in your body, the non cancer cells in your body.
Alan: 33:44 In what way are they hosting the cancer?
Siddhartha: 33:47 They’re not the cancer. By host I mean you are the person who, the human being that is the most [crosstalk 00:33:52]-
Alan: 33:52 Okay. I’m not familiar with that term.
Siddhartha: 33:53 Yeah, it’s just a technical term. Anyway. What if we take the normal cells in your body and convert them, take out something such that now the cancer becomes unique and distinct. In other words, what if you take, rather than focusing on the cancer, alter the normal cells in the body and thereby force or bioengineer the cancer to become unique.
Alan: 34:20 How do you do that without hurting the normal cells? What way do you alter them that doesn’t-
Siddhartha: 34:26 By using CRISPR. You take CRISPR and you delete or you take away a non-essential gene that is on the surface of the normal cell. Once you’ve taken that non essential gene away, the normal cells suddenly lacks it, but the cancer cells suddenly has it and it pops out of the blue. It’s a little bit like saying, as I said, if I could suddenly… The cancer is hiding. Imagine the cancer hiding in a crowd. Now, if I could tell every normal cell to change its color, somehow-
Alan: 34:59 The bad one will stick out.
Siddhartha: 35:01 The bad one will stick out, and now you can use whatever tools you have to kill the bad one. This is exactly how-
Alan: 35:06 How far along are you with this in the lab?
Siddhartha: 35:08 This has now moved beyond the lab. This is now moving into humans. The first in human studies we hope will be launched next year. This is technology that we developed. So this is the example of what I mean, CRISPR and the CRISPR toolbox came out of the hands of basic biologists studying bacteria, studying viruses, not studying leukemia. I’m a leukemia biologist. I sit in my leukemia biology world and think to myself, “What tools are being invented that all of a sudden allow me to make a cancer cell pop out from a crowd.” As soon as CRISPR came along, the idea came along.
By the way, I’m not the only person who thought about it, four or five people, four or five groups, immediately thought about the idea first. We were the first to patent it, so we’re moving it into trials. But it was surprising, perhaps not surprising, the world is obviously full of very smart scientists, but often in making human medicine, we’re waiting for a tool, a technological piece. When that technological piece comes, all of a sudden things switch. That’s very exciting to watch because it’s almost as if that piece of technology turns the whole field on its head.
Alan: 36:35 Right. That is a beautiful thing to see. As you talk, I think about what we humans seem to always tend toward is taking on those tools that you’re talking about, and in a way, seeing if we can get our heart’s desire like super babies. It wouldn’t be a bad thing if I had a super baby that was really super with no deficits in exchange for the superiority. But one of the bad things I can imagine is that super babies, if they’re possible, will be available to people with the money who can afford them, and the gulf between the rich and the poor will probably grow even greater.
Siddhartha: 37:28 Well, this has been a big concern. It’s a big issue, but you already pointed out why it’s going to be very difficult to make super babies in the manner that we were describing before. Most traits that are desirable in societies, and I’ll come back to this word desirable because I don’t believe in super babies myself. I don’t even think that-
Alan: 37:58 You don’t think it’s good or possible?
Siddhartha: 38:01 I think it’s neither good nor possible, but that’s-
Alan: 38:05 If it’s not possible you don’t have to worry about how good it is.
Siddhartha: 38:10 Exactly. Let’s start with the possibility first. You just pointed out exactly the problem. The problem with most human traits that people find ‘desirable’ are carried by so many genes that using CRISPR technology it would be virtually impossible to alter all those genes and making the alteration. You’d be better off finding a partner that had those traits.
Alan: 38:43 Or just send your kid to a good tutor.
Siddhartha: 38:45 Or send your kid to a good tutor, or improve the economic circumstances in which the child was growing up, et cetera, et cetera. You’d be far better. That would be a far less complex solution. There’s a point in my book in which I talk about this. The funny thing about biology is that 20 years ago everyone talked about human malleability, changing human beings by changing environments. They would say, “Change the social environment, change the economic environment.” The funny thing about biology is that it’s taken over the conversation and these days, rather than saying, “Change the social, political, cultural, economic environment,” we’re saying, “Change the biology.” Obviously human traits are a mix of both, there’s biology plus environment.
But it’s surprising to me and rather shocking to me, how much the conversation has twisted and become about the determinism of genetics. “Change the genes and make a better baby.” While you could say, “Well, make a better school.”
Alan: 39:50 That may be harder.
Siddhartha: 39:52 Well, it turns out-
Alan: 39:54 We tend to rely on people to do things like that. People are driven by forces that we still don’t understand as far as I can tell.
Siddhartha: 40:05 Right. But to go back to the technical question or the possibility question, you already identified the problem which is that there are usually so many genes involved, and also chance, and environment triggers involved that simply using CRISPR, at least CRISPR under the toolbox that we understand today, it’s going to be extraordinarily hard to do.
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Alan: 40:30 Well, this all leads me to ask you a question that I really wonder about. It’s getting increasingly easy to predict what your risk of having a disease is. You had schizophrenia and-
Siddhartha: 40:50 Bipolar disorder.
Alan: 40:51 … bipolar disorder in your family. If you knew after a test that… if you could know that you would definitely be suffering from one of these diseases, do you want to know or don’t you want to know?
Siddhartha: 41:09 Two points to make about that. The first point is that I only want to know if I can do something about it. Empty knowledge for me is empty knowledge. Especially because if I can’t do something about it, it will just color my life. It’ll color the lives of my children, my family, et cetera. I prefer not to know if I can’t do anything about it. That’s one. The second is that almost always these genetic tests, aside from the ones that I, couple of examples I gave you, most of these genetic tests turn out to… Because there’s so many genes involved and because there’s such a level of environment and chance involved, they only tend to give you propensities. They will tell you, you have a 40% chance, or a 20% chance, or a 10% chance.
Alan: 41:54 They’re never going to tell you, “This is going be it?”
Siddhartha: 41:56 That’s right. There are diseases in which you can tell this is going to be it, cystic fibrosis being one of them. There are conditions, there are traits where if you have the genetic apparatus for that trait, you will have that trait. I’ll give you other examples, Down’s syndrome would be one of them, Tay-Sachs disease would be another one of those.
Alan: 42:19 Let me counter this with an idea that occurs to me. I mean, I had this suspicion that I had Parkinson’s and a doctor examined and said, “You don’t have it. I don’t see any signs.” I said, give me a scan. I want to make sure. I want to know if I got it, and I did. The reason I wanted to know was if there was anything I could do about it, as you just said, I wanted to be able to do it immediately. But there’s this other thing, you also have to change to begin adapting to it.
Siddhartha: 42:54 Well, there is the question that you can adapt to it. It’s absolutely true. It’s just that, for me, the risk versus the benefit of adapting or knowing early is not sufficient. This turns out to be an intimate decision. This is why genetics is intimate. For some people, the knowledge is important because you can adapt it, you can tell your spouse and say, “Honey, prepare for a particular way that my… this is going to be my life’s journey from now on.” For me it was, gosh, if I found out I had a 70% risk of having schizophrenia in my lifetime, and let’s say I had an episode in which I felt anxious and forgot something-
Alan: 43:43 And you say, “Oh my God, is this it?” That’s right.
Siddhartha: 43:46 Imagine that, not once, not twice, but going on through all of your life. I’m a writer, I have writer’s block all the time. Every writer has writer’s block-
Alan: 43:55 [inaudible 00:43:55] schizophrenia.
Siddhartha: 43:57 That’s right. Every time I had writer’s block, would I say to myself, “Gosh, this is the onset of my schizophrenia,” and that would become a self perpetuating loop because it would give me even deeper writer’s block to know. Rather than getting on a train that had no stop, in my case I made the intimate decision not to explore it. But you’re absolutely right. Some people might say, “I want to know as much as I want to know so I can get prepared for it. Maybe I can be in clinical trial. Maybe I could…” It really depends on the person and their mental makeup.
Alan: 44:34 Well, one of the things we can’t do anything about is… I’m getting the news that we’re at the end of our conversation.
Siddhartha: 44:40 Sadly.
Alan: 44:41 Sadly is right. But we always end our conversations with seven quick questions. Are you game?
Siddhartha: 44:41 I’m game.
Alan: 44:48 This may seem like an odd question given what we already have been talking about, but what is there that you really wish you understood?
Siddhartha: 44:57 I really wish I understood why some cancers are so easy, or are so responsive to treatment, while others are not.
Alan: 45:09 How do you tell someone they have their facts wrong?
Siddhartha: 45:14 I usually go and tell them… I usually like the two-word answer, which is, you’re wrong.
Alan: 45:27 A tidal wave of frankness.
Siddhartha: 45:29 Yeah a tidal wave of frankness. [inaudible 00:45:30].
Alan: 45:31 What’s the strangest question anyone has ever asked you?
Siddhartha: 45:35 Well, I should tell you that it happens to me all the time. For some reason, I don’t know why, people think that I somehow have a good sense of direction and so-
Alan: 45:48 So they ask you directions?
Siddhartha: 45:49 They ask me directions all the time and I’m completely wrong. If you had asked directions from me, the best thing you could possibly do is to walk in the other way.
Alan: 45:59 Well, you [inaudible 00:46:02] developed a line from that old joke, you can’t get there from here.
Siddhartha: 46:06 Exactly.
Alan: 46:06 Then that’ll [crosstalk 00:46:08]-
Siddhartha: 46:08 [crosstalk 00:46:08] them right.
Alan: 46:09 Yeah, that’s right. Okay. Next one. How do you stop a compulsive talker?
Siddhartha: 46:18 I said two words is very good for telling people they’re wrong. A great way to stop a composite of talker from talking is to keep saying the word stop.
Alan: 46:32 Your whole life is CRISPR. You cut it right out. You cut it right to the bone. Well, that’s interesting. Okay, next question. How do you like to start up a real conversation with someone who you don’t know at a dinner party?
Siddhartha: 46:47 I usually like to ask them what they’ve read recently, “What’s the most interesting book you read? Most interesting article you’ve read? Most interesting thing you’ve read recently.” That’s usually, for me, a good segue into several hours until I have to say, “Stop,” repeatedly.
Alan: 47:09 You seem to me like a confident person, so this question is aimed at you. What gives you confidence?
Siddhartha: 47:21 Well, this will sound like a strange answer, but knowing what you don’t know can give you a lot of confidence.
Alan: 47:34 Knowing what you don’t know or not knowing?
Siddhartha: 47:36 Knowing what you don’t know-
Alan: 47:37 Knowing what you don’t know.
Siddhartha: 47:39 In other words, I don’t have any hesitation. First of all, I have no hesitation telling people, “I have no idea.”
Alan: 47:47 Right. Oh, that’s so good.
Siddhartha: 47:51 That was something that Paul Berg taught me and then Alan Townsend, my advisor taught me. It’s a very simple thing to do. When you are confronted with someone who actually knows something about it, the subject-
Alan: 48:04 It’s a good strategy.
Siddhartha: 48:05 It’s a good strategy to say, “I have no idea. Tell me.” If you’re a professor, it turns out you will train people to make you outdated, right? That’s your professional responsibility and your occupational hazard, is that you’re creating people to make you outmoded and outdated. My students who are working on a problem know more about that problem than I do. Whenever I approach them and I say, “Here’s my two bits of advice,” they’ll say, “Thank you Dr. Mukherjee, but in fact you’re wrong.” Then I’ll say to myself, “Wow, tell me.”
Alan: 48:44 Right. Do you feel… I feel a tremendous sense of relief whenever I can say, “I don’t know about that.”
Siddhartha: 48:53 That’s what gives people confidence because you’re not on shaky territory ever. Once you get into territory where you have no idea, you say, “I have no idea.”
Alan: 49:03 Right. You don’t have to defend a guess.
Siddhartha: 49:05 Exactly.
Alan: 49:07 Last question. What book has changed your life?
Siddhartha: 49:13 I would say, stylistically, the book that changed my life the most was probably Primo Levi’s book Survival in Auschwitz, because it’s a story that was written by a scientist, Primo was a chemist. He wrote that and then he wrote a book called The Periodic Table, both of which I find stylistically very important. I couldn’t tell you exactly why they are not related to my books.
Alan: 49:47 What do you mean by style?
Siddhartha: 49:49 By style. I meant there’s an intimacy in the book, but there’s also a critical distance from himself. He sees himself a chemist [inaudible 00:50:03] confined to a camp with a kind of distance. He’s not scathing on himself, but he’s also not overly kind to himself. He’s not scathing to his field, the field of chemistry or synthetic chemistry, but he’s not scathing or kind to it either. Somehow that book will always remain, and has remained, with me.
Alan: 50:28 Well, this conversation is remaining with me, I think, for quite a while. I really had fun with you.
Siddhartha: 50:33 My pleasure. Thank you so much.
Alan: 50:34 Thank you very much.
END CREDITS:
Siddhartha’s first book, The Emperor of All Maladies: A Biography of Cancer, was the winner of the 2011 Pulitzer Prize in general nonfiction and became the basis of a Ken Burn’s series on cancer for PBS.
His latest book is called THE GENE: An Intimate History and it’s the story of the quest to decipher the master-code of instructions that makes and defines humans.
When he’s not writing, Dr. Mukherjee is an assistant professor of medicine at Columbia University and a cancer physician and researcher. To find out more about his work, research, and books, you can visit his web site at:
siddharthamukherjee.com