Interview: Siddhartha Mukherjee, author, Song of the Cell - Hindustan Times
Oncologist, immunologist, cell biologist and author Siddhartha Mukherjee talks about the future of new humans and how the new understanding of cell biology changed the course of cancer therapies
Your third book, The Song of the Cell is the story of the function and the dysfunction of the cell. It's also the story of cellular engineering that has sparked a revolution in biology and medicine. How much of this story is informed by your practice as an oncologist and a cell biologist?
My story is stitched right into every part of the book and ultimately ends with the chapter on the cancer cell — the selfish cell. I'm an oncologist, an immunologist and a cell biologist. There are so many parts of this book that have to do with my personal practice in the laboratory. Obviously, we do a lot of cell biology; we are manipulating immune cells, blood cells and stem cells. So I'd say the book mixes together my laboratory practice, my dealings with patients where we are working on cell therapies and, of course, the history of cell biology.
In the beginning of the book, you mention two of your cancer patients: Sam P, who died of malignant melanoma within a year of his diagnosis; and Emily Whitehead, who was diagnosed with acute lymphoblastic leukaemia at the age of 14, but survived. What do their different fates tell us about the unpredictability of cellular medicines and how do doctors deal with it?
I think both medicine and science are fundamentally unpredictable and, therefore, very interesting. I think doctors deal with it well when they communicate the uncertainties to the patients. "I don't know" is an underused phrase in medicine, but in most cases, we do say we don't know and this book has many signals towards the unknowns. When you start a new field, you see the birth of the new field particularly in cellular medicine there are many unknowns.
Emily Whitehead had almost died and so obviously there are many unknowns. Had they known, they'd have pre-empted things. They were reacting to what was happening in Emily's case. These uncertainties and unknowns lead to new channels of investigations. When they are solved, there are further new channels of investigation and that is very much the practice of medicine. In the field of modern medicine, in particular, when you come up to a frontier, you are blocked at that frontier and then you move to the next one, you find yourself blocked there and move to the next one and so forth until you solve the major problem and you swing to the next problem. So, I do think that there is a fundamental sense that does build into medicine. More and more doctors are saying "I don't know". I think it's a very important part of medical practice.
In the subtitle of the book, An Exploration of Medicine and the New Human, your use of "new humans" is different from their imaginary counterparts in science fiction. What does the future of these new humans, whose bodies and parts are rebuilt with cells, look like?
We're discovering that as we speak. We're learning as scientists to change the bodies of humans in radical ways. We don't think of them as radical because we become a part of the practice of science: the bone marrow transplantation, cellular transplantation, gene generation in various kinds of cells, etc. I think there's a sense that, medically speaking, we are entering new territories. How we reconceive human beings in the context of new territories is going to be not just fascinating, but also disturbing. It could have many ethical implications and humanistic complications, many of which remain unexplored. We are fumbling our way through it as we speak. But we are trying to figure out what this new human looks like.
What effects did the pandemic have on the cell biology of the immune system?
The pandemic revealed things about cell biology that we didn't know before. For instance, there's a whole body of work that shows that some people have underlying defects in their immune systems which were not known and were almost invisible as these people seemed to be working perfectly normally and are only exposed when they are infected with SARS COV 2 or the Covid-causing virus. It was a completely new idea that in viral infections, you might get this phenomenon called the immunological misfiring, where the normal communication between the various wings of the immune system is affected. In the book, I have described the fact that the immune system itself is not just one immune system; it's at least three, perhaps many more, wings.
We used to think that there is a sequential way in which the immune system reacts to a viral infection. One of the things that pandemic revealed is that the sequential way, which seemed very methodical, can be actually dysfunctional and be disrupted by the viruses themselves. And now, a whole new area of investigation has begun to figure out how this dysfunction could be caused not just by Covid, (in cancer it can potentially be used therapeutically), but how other viruses may also be causing the same kind of disruption or dysfunction in the immune system. The pandemic has opened up a new arena of investigation of how these various wings of the immune system coordinate with each other and how potentially they may underline defects long before any infection happens; they are invisible and become visible once you're infected by a virus or a bacteria.
Though it's about a complex subject, the book is quite accessible even for a lay reader. How did you settle on how to tell the story of cells?
I hope it's accessible. There's a lot of very deep information in the book. I use all sorts of tools, metaphors, analogies, diagrams, drawings, mythology — all sorts of ways in which I try to make the book readable, but we're talking about quite difficult things. We're talking about explaining how the innate immune system works now. Whoever has heard of the innate immune system who's not studying biology or biochemistry? We still need to understand it. One very common way to understand is through medicine. No one knows what a SIRI cell is. People may or may not know what an oncogene is, but people have had a personal experience with cancer. Humanising things and making them accessible, using all these tools, allows people a window or almost a window to enter a world that they haven't entered before and, therefore, they enter the world of cytology.
Like all the other books, it has many audiences, who come to this book in different ways. It is being read by cell biologist on one hand, who are exploring the new frontiers of cellular medicine, stem cell biologists, people in medicine, medical biologists, medical theorists, medical atheists, the common public, lawyers, people suffering from diseases, cancer patients, those who are thinking about the frontiers of genesising. The audience is extraordinarily wide and deep and it's written for all of them. So, you have to find a common language that connects all of these people and the common language that I use is the language of medicine that seems to connect everyone and that's how these books get written.
Do you see all your three books so far in a continuum?
There's technically a kind of trilogy and maybe there'll be a quartet of four books. It's a little bit like Star Wars; it's a prequel to the sequel and to the sequel to the prequel. Probably the chronological way to read these books is to read The Gene first, then The Song of the Cell and then The Emperor of Maladies. Of course, it was not written that way. The Emperor of Maladies came first, then The Gene and then The Song of the Cell; you can certainly read the books in that order. There's information that'll overlap and make you understand these worlds in richer and different ways, but this should really be read as a trilogy at this point of time. I'm obviously inspired, though it's a completely different world, by Saytajit Ray's trilogy; you can't see one without seeing the other. You have to understand the antecedents or the precedents. You have to see Appu growing up from a young child in a village to a mature young man and, in the same sense perhaps, you have to see the world of living systems moving from gene to cell to the dysfunction of cells across the three books.
In what ways has the new understanding of cell biology transformed and changed the course of medicine, especially new therapies like immunotherapy for cancer or the infusion of modified stem cells for diabetes?
I think in every way. The two examples that you gave in the beginning are prime examples of the way the cell biology is; the immunotherapy would not be born without an understanding of the cell biology of the immune system. What's interesting is that immunotherapy or immuno-oncology is very much a cell biological outplay; just the genetics or the immuno genetics was not sufficient to understand how to deploy or deliver immunotherapy. We really needed to understand the cell biology of the immune system. You could sequence the human genome which you wouldn't be able to come up with in immunotherapy. You have to understand how the cells of the immune system interact. That's one example in which genetics is insufficient; it is a part, but it's insufficient to deliver or to understand how to deliver or deploy immunotherapy. Another example is pancreatic islet cells that arise from understanding the cell biology of stem cells. How it slowly transforms them potentially into pancreatic islet cells is a very deep cell biological problem and not a problem of just understanding the gene. Genes are important in this; you need to understand how to turn genes on and off in order to make an islet cell out of embryonic cells, but ultimately it's the cell biology that's very relevant. How do you make the cell function as an islet cell? So those are two primary examples of how cell biology is intersecting with medicine.
What are your thoughts on the crumbling health system in the United States? What must be done to make treatments of diseases like cancer affordable?
I think what is important is that the regulatory standards in the countries of Asia that are trying to attempt cell therapy should be rigorous and strict so that we don't become medical tourism for rogue reasons. It's important to have a regulated way so that if patients come here — wherever they come from — there's no proliferation of rogue clinics that'll allow them to do whatever they want while in reality they really should be doing the right thing in terms of cell therapy.
The crumbling health system in America is a long-standing issue. The United States is also the centre for the most innovative therapies and, on the other hand, it's also the country that spends among the highest per capita on health with only marginal improvements in overall lifespan. It has been widely recognised in the United States and there have been a lot of corrective measures, including the focus on prevention, behavioural changes, etc. But there are thousands of reasons for why the health system in America is in doldrums. While it's outside the purview of this book what's relevant is that the forces of renovation are still very much strong in the US and will continue to be strong.
Affordability is a big question for these therapies and that's always going to be there. I am among the many people who are trying to find solutions to the affordability crisis, but that's just one edge of many reasons why the health care system of the US is crumbling. It is a trillion dollar dilemma. We are trying to bring CAR T-cell therapy (a type of treatment in which a patient's T cells, a type of immune cell, are changed in the laboratory so they will bind to cancer cells and kill them), the treatment Emily Whitehead had received, to India and trying to make it more affordable but there will still be many who can't afford it. The problem is that these therapies are intrinsically expensive. There's a ceiling or lower limit to how affordable one can make it. And we're trying to solve this in every way possible.
Shireen Quadri is the editor of The Punch Magazine Anthology of New Writing by Women Writers. She tweets at @shireenquadri.
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