Siddhartha Mukherjee: Can We Reimagine Our Approach To Treating Disease?

Dec 22, 2017

Part 1 of the TED Radio Hour episode Rethinking Medicine.

About Siddhartha Mukherjee's TED Talk

When it comes to medicine, one rule of thinking has generally prevailed: Have disease, take pill, kill something. But physician Siddhartha Mukherjee says treatment should take a broader approach.

About Siddhartha Mukherjee

Siddhartha Mukherjee is a cancer physician and researcher, and an Assistant Professor of Medicine at Columbia University Medical Center.

He is also the best-selling author of many books, including the Pulitzer Prize-winning The Emperor of All Maladies: A Biography of Cancer, The Laws of Medicine, and The Gene.

He collaborated with Ken Burns on a six-hour documentary for PBS based on The Emperor of All Maladies, updating the story with recent discoveries in oncology.

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It's the TED Radio Hour from NPR. I'm Guy Raz.


RAZ: So throughout medicine's most recent history, we've pretty much followed one rule of thinking when it comes to treatment - have disease, take pill, kill something.


RAZ: This is Siddhartha Mukherjee

MUKHERJEE: I am a cancer biologist, cancer geneticist. I run a laboratory on stem cells. I treat cancer. And I write books about cancer and the history of cancer.

RAZ: So you're like the Lin-Manuel Miranda of medicine.

MUKHERJEE: (Laughter) I like that title. Do you expect me to rap?

RAZ: So anyway, that model of...

MUKHERJEE: Disease, target, kill.

RAZ: Which is basically identifying what's bad in your body and then getting rid of it - was made possible by the invention of antibiotics.

MUKHERJEE: Absolutely. And there's a lock-and-key quality to the antibiotic revolution that was so seductive and so tantalizing. So you know, you have a bacterium. The bacterium expresses one protein or some product, and the antibiotic - the chemical latches onto that like a lock and key and really turns it off like a car's ignition engine being turned off. But what a seductive - what a tantalizing idea in medicine. Let's put some chemical and pharmacological background to this.


MUKHERJEE: It's easier to design a molecule that will lodge into a body's protein and shut it off. It's much harder to create a molecule that will lodge into a protein and turn it on. And that's a - it's a fundamental feature of biology - that inactivating things, you know, throwing a spanner in the works is easier...

RAZ: Yeah.

MUKHERJEE: ...Than making a cog work from scratch again.

RAZ: So the - like, the approach to medicine has been that, like throwing a spanner or wrench into the cog and stopping it from moving at least temporarily. Right?

MUKHERJEE: That's right. And one of the things in medicine, which is an important thing to realize, is that we have made better and better spanners, finer and finer spanners that we're throwing into the works.

RAZ: But this model - disease, target, kill - it doesn't work on everything. And it's just a limited example of what medicine could actually do in the future. Here's Siddhartha Mukherjee on the TED stage.


MUKHERJEE: We've really spent the last 100 years trying to replicate that model over and over again in non-infectious diseases, in chronic diseases like diabetes, and hypertension and heart disease. And it's worked, but it's only worked partly. You know, if you take the entire universe of all chemical reactions in the human body, most people think that that number is on the order of a million. Let's call it a million. And now you ask the question - what number or fraction of reactions can actually be targeted by the entire pharmacopeia - all of medicinal chemistry? That number is 250. The rest is chemical darkness.

In other words, 0.025 percent of all chemical reactions in your body are actually targetable by this lock-and-key mechanism. You know, if you think about human physiology as a vast global telephone network with interacting nodes and interacting pieces, then all of our medicinal chemistry is operating on one tiny corner at the edge - the outer edge of that network. It's like all of our pharmaceutical chemistry is a pole operator in Wichita, Kan., who's tinkering with about 10 or 15 telephone lines. So what do we do about this idea? What if we reorganized this approach?


RAZ: On the show today, ideas about Rethinking Medicine - exploring new ways we can treat diseases, transforming how we understand the human body and improving - and hopefully even saving - lives. And for Siddhartha Mukherjee, rethinking medicine means rethinking the way our bodies heal. Siddhartha says we need to move away from what he calls a going-down model to building-up.

MUKHERJEE: The going-down model is disease, target, kill - you know, pneumonia, bacterium, antibiotic. The building-up model is to start from base up and say, what's the environment that the organism lives in? What's the cellular or physiological environment that the organism inhabits? And what are the connections between cells that sustain normal physiological interactions in life? Look at vaccination. Vaccination is a profoundly successful medical intervention. But it does not belong to the have disease, where is the target? - let's kill something.

RAZ: Right. Of course. It prevents it from happening in the first - yeah.

MUKHERJEE: It's preventing, and it builds up. It builds the immune system up. It builds up your capacity to reject a pathogen such as human papillomavirus, which causes cervical cancer, or influenza virus. So this is just to remind us that outside this disease-target-kill model, there's a whole universe of regenerative medicine, nutritional medicine, preventative medicine - a model of creating health from the ground up.

RAZ: So in other words, it's not just about thinking - for example, with cancer - of the precise tumor that you are targeting - which you would continue to do - but the environment that that tumor lives in and the other things that may be contributing to that tumor's survival and growth.

MUKHERJEE: Absolutely. So this is an old idea. It's called the seed-and-soil hypothesis. And for a long time, cancer biologists loved to work on the seed, the cancer. But of course, that seed only grows in certain soils. There was a real mystery as to why. Just to give you one example of how many mysteries there are, breast cancers metastasize to bones but don't metastasize to certain other organs. The liver gets lots of metastases. But the spleen, which is an organ of similar size, gets very, very few metastases. What is it about one organ versus another that forms the right soil for cancer?

So these questions have obviously existed in biology for a long time. But because of cancer genetics - because we were so interested in the genes within the seed, the cancer cell, we focused our attention on the cancer cell. And that's helpful. This is the yin-yang quality to all of this. But it's now important to think about the soil. And it's important partly because - actually, when I gave the talk, I didn't realize this but since then, among the most successful therapies in cancer are immune therapies...

RAZ: Yeah.

MUKHERJEE: ...In which you activate the immune system against the cancer. Now if you really think about it, immunes therapies are soil therapies. They are making the soil, the environment - the microenvironment that the cancer grows in - less amenable or less hospitable for the cancer cell to grow. So that's a soil therapy.


MUKHERJEE: What's really at stake, perhaps, here is not the medicine itself but a metaphor. Rather than killing something in the case of the great chronic degenerative diseases - kidney failure, diabetes, hypertension, osteoarthritis - maybe what we really need to do is change the metaphor to growing something. And that's the key, perhaps, to reframing our thinking about medicine. And it raises a series of, I think, some of the most interesting questions about how we think about medicine in the future.

Could your medicine be a cell and not a pill? How would we grow these cells? Could your medicine be an organ that's created outside the body and then implanted into the body? Could that stop some of degeneration? Could we store these organs? Would each organ have to be developed for an individual human being and put back? And perhaps most puzzlingly, could your medicine be an environment? Could you patent an environment? You know, there's been - in every culture, shamans have been using environments as medicines. Could we imagine that for our future?

I've talked a lot about model-building. That's what we do as scientists. You know, when an architect builds a model, he or she is trying to show you a world in miniature. But when a scientist is building a model, he or she is trying to show you the world in metaphor. He or she's trying to create a new way of seeing. The former is a scale shift, and the latter is a perceptual shift. Now, antibiotics created such a perceptual shift in our way of thinking about medicine that we - it really colored, distorted very successfully the way we thought about medicine for the last hundred years. Well, we need new models to think about medicine in the future.


RAZ: I mean, if you're a researcher today and you're looking at cancer treatment - right? - are you focusing on treatments to kill the cancer, or are you focusing treatments to think about the environment - targeted therapies? Or are both happening?

MUKHERJEE: Both are happening, and both should happen. One of the seductions of cancer genomics was to focus and perhaps refocus our attention on the seed, on the genetics of cancer. What genes - so the question we would ask in the clinic five, 10 years ago - what genes are driving this cancer cell? How can I shut those genes off?

RAZ: Yeah.

MUKHERJEE: Now we're asking somewhat different questions. We are saying, how is the cancer cell - with its driving genes - surviving in this host? What allows it to do that? Again, this is to emphasize that these are complementary questions. And if you were to ask me, projecting ahead, my suspicion would be that the only long-term way to think about this is to use them in this yin-yang way. On one hand, inhibit, kill, suppress the growth of the cancer. But on the other hand, allow immunology, the microenvironment that the cancer grows in to reassert its normalcy.

RAZ: Yeah. I mean, you are still a relatively young man in your field. And so it's pretty remarkable. It sounds like there's been an enormous change even in the way that you have thought about the work you do 20 years ago and the way you think about it today.

MUKHERJEE: One enormous change is - for me, in particular - I'm a cancer biologist. I grew up in the era of cancer genomics. My laboratory has identified certain cancer genes. Recently, I was differentiating along the pathway of, you know - find the gene, find the target and try to identify what to do with the target.

RAZ: Yeah.

MUKHERJEE: About five years ago, my own research practice - and my clinical practice - took a very big change. I started thinking about nutrition. I started to think about microenvironment in cancer. What about the inflammatory environment? So in 2010, we published a paper in Nature showing that if you change the environment, you can actually change the behavior of the cancer in dramatic ways - leukemias - in dramatic ways.


MUKHERJEE: My lab now has a wing that works on immune system in leukemia. You know, 10 years ago, we were all working on genes - you know, genes that cause leukemia. And we still do, hoping to find targets that will kill the cancer cells. But we've more and more started thinking - well, what about the environment that the cancer grows in? And my laboratory has undergone a complete change in these last five years.

RAZ: Siddhartha Mukherjee - he's a cancer biologist, physician, researcher and author of "The Emperor Of All Maladies" and "The Gene." You can see his full talk at On the show today, ideas about Rethinking Medicine. I'm Guy Raz, and you're listening to the TED Radio Hour from NPR. Transcript provided by NPR, Copyright NPR.