Mukherjee and Hudis on Emperor's Journey to PBS

Siddhartha Mukherjee, MD, PhD; Clifford A. Hudis, MD

Disclosures

March 17, 2015

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Editor's Note: As traffic sounds rose from New York City streets, Clifford A. Hudis, MD, chief of the Breast Cancer Medicine Service at Memorial Sloan Kettering Cancer Center, and past president of the American Society of Clinical Oncology, sat down with Siddhartha Mukherjee, MD, PhD, to discuss his writings, the much-anticipated documentary Cancer: The Emperor of All Maladies, and what the present moment in cancer research means for science and society.

Dr Mukherjee, who told Medscape Editor-in-Chief Eric Topol, MD, about the documentary last spring, returns to talk in-depth about the ambitious documentary, which will air on PBS on March 30, March 31, and April 1.

Clifford A. Hudis, MD: Hello. I'm Cliff Hudis for Medscape. I'm pleased to welcome a special guest today, Siddhartha Mukherjee, author of the Pulitzer Prize–winning book The Emperor of All Maladies and co-producer of Ken Burns' 6-hour documentary of that book, which will air at the end of March. Sid, welcome.

Siddhartha Mukherjee, MD, PhD: Thanks for having me.

Dr Hudis: Sid, you started writing Emperor in 2004. It's been more than 10 years and the adaptation of the book is coming out now as a 6-hour documentary. How does this make you feel? Did you imagine that that book would lead to this project?

Dr Mukherjee: Absolutely not. Everything in the project has been a surprise, including the developments of science and medicine that occurred while we were making the film. They were all surprises. Obviously, when we started a project like this, we never imagined which direction it would go in, but I'm so delighted that this came about.

Dr Hudis: What would you say was your primary goal? All of us in science write papers. You sat down with a blank piece of paper and a pen. I've even heard stories about you writing this at the end of the work day. What were you aiming for in the beginning?

Dr Mukherjee: In the beginning, the book was a very different kind of book. I was keeping a journal. I was a fellow as you've been, as all of us have been, nose to the ground doing the usual things that you would do every day: writing orders for chemotherapy and trying to figure out how to best help our patients. In the middle of all of this, I was struck by a small comment. I think every book or every creative project really begins at one moment.

For me, that moment was when a woman came up. I was treating her. She was on a third round of a kinase inhibitor trial for an abdominal sarcoma. She said to me, "I can go on, but I need to know what it is that I'm fighting." It struck me that I had no real tools to answer that question. How had we gotten here, to the point that she was being treated on a third-generation kinase inhibitor? What was to happen next? What did the landscape look like? That's how the book started.

'No Science Outside of Storytelling'

Dr Hudis: That story is, I think, emblematic of the messaging we want to get out and that science has been relatively bad at. We don't often tell our stories to the general public all that well, all that clearly. Both the documentary and the book are really powerful examples of storytelling. How important is the storytelling aspect of all of this to you? In other words, could this history have existed if not for the personal stories that are woven through the book and the documentary?

Dr Mukherjee: It couldn't. The entire thrust of the documentary and the book is that all of this should and can be achieved by storytelling. I also would make the argument that there is no science outside of storytelling, and they are fundamentally linked.

If you ask the greatest clinicians, the greatest scientists, about their most innovative work, they describe that work not in some kind of abstract equation, but they describe that work in terms of storytelling. They tell you exactly what made them think of something, what its history was, how they arrived at the idea, and how they then incorporated it into their own stories.

You can't imagine medicine outside storytelling—at least I can't imagine it—and that's how I structured the book. And the documentary is story upon story upon story. It builds from there.

Dr Hudis: Turning to the documentary, how did that project as an outgrowth of the book actually get started? And as co-producer, this is a role that most of the clinical audience really has no insight into. What did you do as a co-producer?

Dr Mukherjee: The first piece—how the documentary got started—is an interesting story. Before my book was formally published—it was big sheath of papers that landed on the desk (and I actually still don't know how) of Laura Ziskin, who was running Stand Up To Cancer. Unfortunately, she died. She was an amazing producer and had a great vision but was undergoing treatment for metastatic breast cancer at that time. As the head of Stand Up To Cancer, she called me up—cold call on the phone. I was sitting in my office in New York, and she said, "I'm Laura Ziskin. I'm at the Crosby Street Hotel. Would you come here within 2 or 3 hours? I want to discuss turning your book into a documentary." I said, "Sure, I'll come." So I took the train down.

Dr Hudis: This is a reminder that we still take the subway.

Dr Mukherjee: That's right. And it's a reminder that we still answer our own phones, which is important.

Laura said, "We have to convert this into a documentary. I know how to do that." I said, "That's absolutely wonderful. That's incredible." I went back and was still thinking about Laura's offer—this is the real story, truth being stranger than fiction—when 2 or 3 weeks later I got a phone call. Again, a cold phone call in my office, from Ken Burns saying, "We want to do this as a documentary." I said that these two projects have got to come together.

So Laura and Ken collaborated. Actually, the PBS team collaborated in putting together the documentary, and it was one of the amazing public‒private collaborations, between Stand Up To Cancer, PBS, and WETA [Washington, DC, public television affiliate, which coproduced the documentary. WETA president and CEO] Sharon Rockefeller was the person behind the WETA aspect of the project. That's how the whole thing came together.

Capturing a Breakthrough in Real Time

Dr Mukherjee: Technically, I'm not a co-producer of the film. My role has been to be the advisor on the script, to make sure that the story was told in the way that's true to the book and true to the history. I stayed with the documentary from day 0 until the very last edit of the very last cut. I must have seen it with Ken and Barak [Goodman, director of the documentary] 26 times, fine-tuning every single aspect, making sure that the stories were balanced and appropriate, but that they also retained that urgency of storytelling, crucial to any project in medicine.

Dr Hudis: One of the things you just said caught me by surprise. I want to make sure I heard it right. Were you actually the connector between Ken Burns and Laura Ziskin?

Dr Mukherjee: I was the connector between Ken Burns and Laura Ziskin.

Dr Hudis: That's really a remarkable fact, which probably wouldn't be clear to people.

Ten years is a long time, and the past 10 years have been very exciting in science. How have you molded or reshaped the story from what you wrote to what is relevant today? There are areas of scientific work, translational science, and clinical results that were only dreams 10 years ago.

Dr Mukherjee: That's absolutely right, and that was one of the most interesting things about the project: It was an opportunity to update the book. Like any other work about science, I knew the science—the content—would overtake the book at some point, but the form would remain the same. The mistakes that we make, the way we acquire information, the cycle of innovations remain the same. So, that lives on in the book: the form of the way we discover things.

In terms of content, of course, things change. One of the most exciting things while making the documentary was that new fields came alive—the whole field of immunotherapy. People had been looking at immunotherapy, at using the immune system to attack and kill cancer. But it was sort of a dream. It came clinically alive while the documentary was being made. We actually had to change the script. When we first wrote the script, immunotherapy was there but it was the tail end of the script: What a nice fantasy it would be if you could train your immune system to recognize and kill cancer cells. While the film was being made, that fantasy began to become real—not in every case; there were some ifs, ands, or buts with that kind of therapy—but we saw it come alive.

So the script had to be changed to reflect that, and a 4-minute segment became a 20-minute segment that bookends the film.

Contemporary Patients and the History of Cancer

Dr Hudis: In a sense, the documentary can't be a pure retelling of the concrete stories in the book. It has to have evolved to incorporate new science.

Dr Mukherjee: It had to. That was the plan upfront. We decided we would not copy the book. We said that we would have stories that were current, that were based in the present in the film, and the film would go back and forth between those contemporary stories and the history, so that you would understand what the links were between work done in the 1950s and the treatment of a woman with breast cancer in 2015. Those two things would come alive in a way that wouldn't if you told the story sequentially or narratively. We made a very upfront decision that the film would be intercalated this way; you would go back and forth between history and contemporary stories.

The second thing that I think is very interesting about the filmmaking—going back to your question about storytelling—was that the camera teams, based on an agreement with Hopkins and with a community hospital in the South, were embedded in the hospitals, so that patients who had given their permission would allow us to film them on day 0 of their diagnosis and follow them longitudinally forward. It wasn't told retrospectively. We followed them as their stories unfolded, and that was incredibly powerful. You feel the urgency interposed against a deep history.

Dr Hudis: I'm curious to see—and I'm sure many people will be—the focus that you just described, which is compelling. But there's a risk in that [type of storytelling] for everybody involved, even those patients who are fortunate enough to benefit from impressive breakthroughs. Some diseases have been transformed; what used to be a near death sentence can be a chronic illness. That's true. But as we know in other diseases, we get remarkable responses that are unprecedented and we see benefit, but we still unfortunately can have a sad ending. How did you cope with that in terms of the context of public storytelling and without, let's say, raising the hope too far or dashing it too much? How do you manage that balance?

Dr Mukherjee: The mood in the documentary has to be faithful to what's happening in medicine. There was some sobriety about it. The optimism had to be balanced against what was sobering. The point was not to flinch from what's been tough. So, you witness, not on camera, but you know when patients die in the film. We didn't want to invade privacy, but on the other hand, we didn't want to sugarcoat a story which is very, very complicated—with enormous strides for some patients, transformative medical therapies for some patients, and yet no success for others.

You will watch on camera really tough moments when patients face their death and when medicine faces its failures. This has got to be shown. If you don't show it, you create a sugarcoated version of reality, and that was not the purpose.

Truth-telling in Film and Medicine

Dr Hudis: I think that can be very helpful, because one of the issues that we've talked about in the past and that I focused on [in my presidential address] last year at ASCO is the partnership between society at large and the scientific community, which is really focused on solving these problems—let's not be unclear—for society. There is not a difference between science and society. We are part of society. So, by telling these stories, one hopes that we will engage all of the public in providing more of the kind of support that we need to accelerate the already impressive advances that we've been seeing.

Given your vantage point, how do you see us doing that? What would you advise our community of scientists and physicians and translational investigators to do? This is one important step. How do we leverage this to do more and to do it faster, do you think?

Dr Mukherjee: The most important idea in this is truth telling. When medicine gets oppositional with its own conclusions, when it tries to hide what's known and what's not known, I think it just gets into deeper and deeper trouble. [What’s better is] the openness of telling people that these have been transformative advances but there's still a lot to do.

Our biggest asset is hope, but it's also our biggest vulnerability because we so badly want this to happen. We so badly want to find a cure that hope gets in the way. We try to describe to people and want them to be hopeful but, of course, there's a balance between providing the right kind of hope and blowing it out of context. I think that balance is very hard to reach. As long as you're honest, I think that's very helpful.

Dr Hudis: You touched on something that is profound and hard to convey. I think the film will resonate for many of the professionals who watch it and I suspect for patients as well. But that fine line between honest hopefulness and truth-telling that doesn't destroy hope is tricky. It varies for each patient and each family and their needs. I think this documentary should help contribute to that openness.

Dr Mukherjee: That's what the art of medicine is. Great clinicians know how to do this. I actually describe in the book watching someone like Tom Lynch [thoracic oncologist and director of Yale Cancer Center] do this—never destroying, never asphyxiating hope, but never creating a false impression of what's available and what can happen. It's the art of medicine.

Dr Hudis: If you're really a sensitive clinician, you never think you've quite got it right.

Dr Mukherjee: Yes, that's right.

Innovating an Access to Care

Dr Hudis: I think that's really true. At this time in our scientific development, we're very focused on technology, new views of medicine, new views of drug therapy. And costs are something that are increasingly focused on, transparently and openly. As you bring to light the remarkable advances of the past few years, how do you think we can address what I consider to be one of our intentions, which is access to care and availability?

Dr Mukherjee: The issues of access are complicated. On one hand, there is the issue of access to even the basic level of healthcare. In oncology, you're talking about much more complicated healthcare and often much more expensive medicines, particularly if you're talking about the newer medicines.

Again, the question is finding a balance. We covered access in the documentary. There's a section that was dedicated to access to inform people how complicated it's gotten for patients to be able to access the medicines that they need, especially the newer targeted therapies or immunologic therapies in terms of the cost. So, I would encourage you and others—you'll see the issue coming alive in the documentary.

Dr Hudis: Yes, I think this is going to turn out to be a really important issue because, again, it has to do with who's paying and for what. We all benefit from everyone getting the highest quality of care. I'm reminded of a side issue: that copays actually diminish people's compliance with really transformative drugs, such as imatinib, which the clinical audience will know. It makes no sense to have a financial disincentive to compliance.

Dr Mukherjee: Yes.

Dr Hudis: And it doesn't make sense for society. I wonder if you've had some thoughts about that. How much are we able to engage in discussion about, let's say, continued reform in terms of insurance coverage?

Dr Mukherjee: You know I certainly am not the expert in insurance coverage, but the thought that I've had several times is that as someone who is a physician scientist, a translational scientist, our job is to improve technologies to the point where the wastage is limited. In other words, if you're [not] giving medicine to someone who won't benefit from that medicine because of their genetic makeup, that can vastly improve the quality of access. Access isn't just [an issue of] money; it's giving the right medicine to the right person at the right time for the right disease.

Dr Hudis: That's precision medicine.

Dr Mukherjee: That's precision medicine. From the standpoint of science and innovation, I think we can contribute to access enormously. We can't solve the right-price problem, but we can solve the right-person problem and the right-medicine problem. I think pharmaceutical companies can and will solve the same problem. Inventing yet another ineffective drug that increases lifespan by 2.5 weeks and pricing it at some gigantic number is not going to solve the problem. On the other hand, if you target the right patient with the right medicine and you can increase their meaningful life by 5 years, then the whole access discussion becomes very different.

Dr Hudis: Yes. I think that's a very profound way to look at it, and I agree with you. One of the frequent concerns is whether worrying about this issue will diminish the enthusiasm and investment in innovation. That's an important point.

Dr Mukherjee: This is absolutely incredible.

Dr Hudis: We can't let that happen.

Dr Mukherjee: No, it's absolutely incredible. Speaking to the people who think about translational medicine and innovation cycles, the issue of access should make us even more excited. This is a problem that, as I said, can be solved by figuring out the money part of the equation. But on our end, we have to figure out the right person part of the equation, the right science. I think it's exciting. It's innovation. I mean, you have to innovate yourself out of the access problem, and I don't think we're doing that appropriately right now.

The Three-Zeroes Problem

Dr Hudis: I think that's a very good way to look at it. I agree with you. Now, thinking about resources, which is what we're talking about, as you know and many in the audience will know, the past 10 years have not been so great for federally supported cancer research. Other resources have been brought to bear, but as you know, a rough estimate is that we've lost about 25% of the purchasing power at the NIH and that's also true within the NCI component of the NIH budget.

At the end of January, President Obama called for new spending of about $215 million in precision medicine, the topic we've been covering. This will get split into different domains. It covers not just oncology but also other areas of medicine.

Dr Mukherjee: Absolutely.

Dr Hudis: A challenging question that many laypeople will ask is, "Okay, Dr Mukherjee, here's a blank check. How big does it have to be? What proportion should go where?" How do you think about that problem?

Dr Mukherjee: There are greater minds at work on this problem. But just to give you a sense of what their numbers look like, $215 million is a very small amount of money. I call it the three-zeroes problem. After $1 million, for most people, an extra three zeroes and an extra six zeroes make no difference. But we have to discriminate between these two.

The Medicare budget, for instance, is several trillion dollars. That's another six zeroes after a million. [With $215 million] you're talking about a much smaller amount of money. Just to give you another sense of what the numbers might be, the budget of the NCI and the NIH is on the order of $5 to $10 billion, right? So with [$215 million] you're not adding an enormous amount to this pot of money for a very important initiative, which is precision medicine.

Now that that's said and done, cancer has led the road in precision medicine because it is the most genomically annotated disease. We know more about the link between the genetic makeup of cancer and its capacity to respond to certain therapies. Obviously, cancer is going get a chunk of that [precision medicine money] because it's a huge clinical problem. I'm glad that that initiative has started. But I think it's underfunded. I think $215 million sounds like a lot of money, but for the scope of the problem, which will affect, as you know, 1 in 3 men and women in the country, it seems enormously underfunded. But I'll let smarter minds decide how much to take on.

Dr Hudis: Well, you're preaching to the choir, of course. One way to think about that three-zeroes problem is that the federal budget is around $4 trillion a year and the NCI budget is around $5 billion a year. To a first approximation, that makes it 0.1% of spending on a problem that, as you rightly point out, affects one third to half of all Americans.

Dr Mukherjee: It's highly disproportionate.

Dr Hudis: I don't know what the right number is, but it doesn't feel like our spending on the problem is commensurate with the challenge we face.

Dr Mukherjee: Absolutely not. No, it's not.

Dr Hudis: One of the subtleties that we're going to confront in the coming months is whether that money is new money, even as modest as it is, or whether it's carved out from existing medical science programs. Because in the latter case, we're robbing Peter to pay Paul, and that, to me, would be a frustration even though it's a noble intent.

You mentioned—and you're right, of course—that the reason cancer has been leading so much of this precision medicine initiative is the ability to study the genome and to relate changes in the genome of the tumor against the inherited genome and, in turn, against the natural history of the disease.

In fact, this is a natural segue to your next book, which I understand comes out later this year, which has a more narrow focus—the human gene. Can you give us a preview of what it is that you talk about there?

The Future Inferred From Shadows

Dr Mukherjee: I'm trying to write a history of the gene as a 20th century idea. I was intrigued by the idea of something that was discovered by accident by a myopic monk in Europe in the 1860s.

Dr Hudis: You're referring to Gregor Mendel.

Dr Mukherjee: I'm referring to Mendel, yes.

Dr Mukherjee: But by the 1960s, 100 years later, the discovery becomes the centerpiece of discussion around health, disease, identity, choice, personality, temperament, illness—issues that are very much at the core of human beings. From the 1960s onwards, the gene becomes a locus that is potentially changeable, and the power that that gives, the way that changes the basis of conversation.

That very large history is juxtaposed on—and I won't tell you all the details—a very personal history. The book goes back and forth between that very large voice of history and the very small voice of personal history.

Dr Hudis: One of the things that has always impressed me has been the depth of insight that early investigators were able to reach, without any of the modern tools from x-ray crystallography now to PCR and so forth. And yet long before the double helix was actually described, its nature was inferred; the structure and function of genes were described decades before anybody could see them. Do you touch on that?

Dr Mukherjee: Absolutely. What's interesting is that Mendel didn't even have the word "gene." "Gene" was coined in the early 1900s. Mendel just saw a statistical shadow. Again, with this book, as with Emperor, the question that I'm very interested in is: What things are we now seeing as shadows but which will become relevant or apparent 10 years or 50 years from now? What are these shadows today? They're interesting ideas: The future or fate of human gene therapy for medical diseases we can just see as a glimmer of shadows, as it were, after enormous failings. So, those ideas are very much in the book. What is seen before it can be seen? How do we see things before even technology can anticipate them?

Dr Hudis: One of the things I got out of our conversation just now, which I didn't get out of the book—maybe because I just didn't see it—is the constant nature of human behavior and the way we learn, as opposed to the specifics [of what we learn]. Because what you're really describing over the decades is that the tools change, the pace of advance at times accelerates and at other times doesn't. But the way we process new information and incorporate it, the way we learn from what we see, does seem to be pretty much the same.

Dr Mukherjee: That is the center of this book and that is the center of the last book. It's not what we learn; it's the way we learn, and that's going to be constant. I argue and will continue to argue that that's going to be constant for the foreseeable future of human beings—not what we learn but the way we learn.

Dr Hudis: Our genes make us that way, right?

Dr Mukherjee: That's right.

Dr Hudis: Well, I have to say that I'm sure your new book is going to be as enthralling as the last one.

Dr Mukherjee: I hope so.

Dr Hudis: So now that you've seen what can happen, do you imagine a documentary about the new book also?

Dr Mukherjee: Well, the book will have to be finished first. We have to take a step back.When you're so close to a project, you can't even see beyond it.

Dr Hudis: Sid, congratulations on this. Thank you very much for spending this time talking to me and to our audience today.

Dr Mukherjee: I appreciate it. Thanks a lot.

Dr Hudis: It's really been enjoyable and enlightening I hope for everybody, but certainly for me.

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