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Siddhartha Mukherjee on the rapid pace of cancer research



The first cells Siddhartha Mukherjee ever saw were T cells, pulled from a mouse spleen and plated onto the microscope slide, given chemicals to coax them to grow. When he looked down the scope, he was struck by the life in them, marveling at what he called their “inner glow and luminous fullness.”

That thrill Mukherjee feels each time he sees life under the microscope carries into his new book, “The Song of the Cell.” The book is at once a kind of freewheeling adventure through the history of the cell — from the first microscopes to the highly engineered CAR-T cells that cured once “incurable” leukemia patients — and a personal reflection on human health, disease, and the rapid pace of cellular medicine.

“The excitement of this world is the excitement of those therapies and how it could be actualized,” Mukherjee said. “I, myself, have been doing a lot of work on cellular therapies and genetically modifying cells. So there’s been a range of really exciting changes in cell therapy that I’ve witnessed that have also gotten in this book.”

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As the founder of several biotechs and a practicing oncologist, Mukherjee has a front row seat to the changes taking place within medicine and the field of cell therapy as it sprints forward.

“We’ve sequenced virtually the entire genome. The question arises, what do we do with this information? For a cell biologist, it represents an interesting challenge, you can’t look at the genome and say why metastases go to the liver and not the spleen,” he said. “You have to look outside human genetics, in general, to answer fundamental questions about development, disease, cancer, and ultimately how we’re built.”

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STAT spoke with Mukherjee about these ideas, cancer, and his new book. This interview has been edited for length and clarity.

In some ways, this book is a continuation of your last one, “The Gene.” What was the impetus for exploring the cell here?

The gene is lifeless without something to bring it to life. The gene is the score; the cell is the musician that brings it to life. That’s the ‘song’ of the cell. So, that was one impetus. The other, of course, was cell therapy. In the last four years, it’s become real medicines ranging from genetically engineered cells to cure blood diseases, those are CAR-T cells, to new companies and labs sprouting up to assembling all kinds of tissues like artificial pancreatic tissues. That’s the excitement.

Then ever since the cell was discovered, there were metaphysical inquiries into life and the cell. Is it autonomous? Is it aware? What are its emergent phenomena, when groups of cells come together and become an organism? So that’s the metaphysical component. The cell — and the body — are properties of life. It embodies it, and it is life.

The book has this modular structure, kind of mimicking the compartmental organization of the cell or a multicellular organism. Was that some of the intent?

That was the real challenge — how to structure the book. It’s not told chronologically, but as a series of short stories — a series of love letters to different cells. It had to be done this way, because everything is happening at the same time.

Each chapter is a mini history and a story of its own making. It takes on the personality of the cell, why is it there, what is it doing, and what are we doing to it? A neuron functions nothing like a T cell, though they have channels, membranes, and synapses in order to touch other cells.  Every chapter, you get all of that from a type of cell, sometimes told through the story of discovery or through a patient.

You weave in these stories from your personal history and your experiences as a physician into the way you understand the cell. Can you tell us a little bit about that?

I’m simultaneously a biologist, cancer scientist, doctor, and in some parts of the book, a son. I thought it’d be a strange book where those elements of my life, the medical elements of my life were not woven into the book: my own experiences with my friend dying from cancer. My own experience with depression leads to a [deep] examination of how neuronal cells achieve their very complex cognitive and other functions. There’s an incredible scene, almost from Macbeth, in which I’m drenched in blood as a young resident from someone who is bleeding from varices.

All of that, I think, is important because it gives context about how cell biology, even when you don’t think it’s there, is entering into our lives. And if those parts were not there, the book would feel sterile, not like a living object, not like a cell.

The chapter about cancer is called the ‘Selfish Cell.’ Can you talk about how cancer is sort of like the ultimate disease of the cell and how it exists as this perversion of life?

If you think about the three great principles of life — evolution by natural selection, genetics, and cell theory — cancer is the one disease that sits at the intersection of all three. It’s an evolutionary disease, a cellular disease, and ultimately it’s a genetic disease. I call cancer cells the selfish cell because throughout the book, we meet cells that are cooperating with each other.

Pancreatic cells expend energy to send out — to make and send out a molecule called insulin from the pancreatic beta cell. It’s at an expense to itself, but it does so that the entire body can know when there’s glucose in the body. It’s a selfless act, actually, since it’s acting as part of the whole organism. Cancer cells don’t obey these laws. It goes where it goes, metastasizing to the brain, bone, going where it has no place to belong.

So, it’s following its own rules, wanting to survive, grow in the organism, at the expense of the whole.

What are some of the most exciting things in cell biology and cancer, now, and where do you see it going?

I’ve been working on creating and inventing ways to treat leukemia using genetically modified cells. Through a company, Immuneel, I’ve been introducing cell therapies, CAR-T, to India. That was one of my proudest moments. Then I’ve also founded companies that potentially change cellular metabolism in cancer or the biology of myeloid cells so that they can attack cancer. There’s been really a range of exciting changes in cell therapy that I’ve witnessed myself that brought me to this book.

Just look at the burst of energy brought by stem cells. These fields once seemed impossible. The idea of reprogramming a cell, a stem cell — it’s an incredible idea and so deeply exciting. If you were to go to someone four decades ago and tell them about it, it’d seem completely absurd.

I write about the historical context of all this, though, because it allows us as contemporary thinkers to understand what the processes look like but also draw parallels to what’s missing today and what kind of new microscope we’d like to build.





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