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Shumita Basu, Narrating: Grief is one of the most universal of human experiences, and yet we don't talk about it very much. Instead, we are often left feeling alone with our sadness. That's why CNN's Anderson Cooper is choosing to talk about grief, be direct with it, in his new podcast. He talks with people about those they've lost, things they've left behind and how we can coexist with loss, with love and with laughter. Listen to "All There Is" with Anderson Cooper on Apple podcasts.
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Basu, Narrating: This is "In Conversation," from Apple News. I'm Shumita Basu. Today, how our understanding of cell biology is redefining what is to be human.
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Basu, Narrating: In 2010, six-year-old Emily Whitehead was diagnosed with ALL, acute lymphoblastic leukemia.
Siddhartha Mukherjee: It's a blood cancer. It's extraordinarily aggressive, one of the most aggressive cancers that we know.
Basu, Narrating: Siddhartha Mukherjee is a cancer physician and researcher at Columbia University. He's been following Emily's story for years.
ALL is the most common childhood cancer. Treatment involves about two years of an extremely aggressive chemo regime. 90% of pediatric patients with ALL end up being cured.
Mukherjee: Emily, unfortunately, was not in the percentage that was cured by standard chemotherapy. She went through second line, was not cured, and then she relapsed again. And that is, or was, absolutely deadly. The chances of anyone surviving relapsed refractory ALL was basically zero.
Basu, Narrating: So Emily ended up being enrolled in a clinical trial at the Children's Hospital of Philadelphia. In this trial, Emily's own T-cells were extracted, modified to recognize and kill her cancer using gene therapy, then put back into her body. This treatment had never been tested in a child before, but ultimately it worked. Emily's been considered cured for over ten years now.
Mukherjee: I spoke with the family just last week to congratulate them on her applying to college.
Basu, Narrating: Sidd wrote about Emily in 2011 in his Pulitzer-Prize-winning book, "The Emperor of All Maladies," and he revisits her story in his new book, called "The Song of the Cell: An Exploration of Medicine and the New Human." It's a deeper dive into what's possible in a world of advancing cellular therapies.
Mukherjee: I think we are on the verge of redefining what human is and what human abilities are.
Basu, Narrating: Now, this idea of the new human may sound like science fiction, but Sidd argues cellular therapies have already created new humans, people whose cells have been modified, like Emily Whitehead or anyone who has undergone a blood transfusion or bone marrow transplant.
But as the science continues to develop, it keeps pushing up against the question of what we should be able to correct for. Where's the line between alleviating suffering and optimizing for preferences? Let's back all the way up and just talk about the human cell. Because it's an incredible thing, as Sid will tell you, especially when you see it up close.
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Mukherjee: So the first time I really saw a cell is when I moved to Oxford and I started working as an immunologist and, you know, there was this one dark room where the microscope was kept. So I, you know, turned on the microscope and, for the first time, saw a T-cell that I'd cultured. And it's-- For a cell biologist, I mean. I don't know what it's like-- what it's like to see a cell if you're not a cell biologist, but for a cell biologist there's something spiritual about that experience. And it sounds kind of silly to say, looking at a cell as a spiritual experience, but there's something to looking at life extracted out to its basic unit and realize that the thing staring back at you from the microscope, this oblong thing which is glowing usually, is actually alive, and actually constitutes a part of you and me. And if it wasn't there, you and I wouldn't be whole. We wouldn't be full. We wouldn't be complete. And the best thing is, about these T-cells that we were culturing, they move. If you're patient enough, you can see them crawling around a dish because they're alive. And if you're really patient, you can see them doing their real job. In this case, these are killer T-cells, you can see them kill a cancer cell. So, anyway, that was my experience of looking at cells.
Basu: I've never heard anyone use such human-like or animal-like descriptive language for-- to describe what a cell can do. Maybe you can actually just remind people, at its most basic level, what is a cell? What is remarkable about understanding what a cell is?
Mukherjee: A cell is the basic unit of life. It is the basic single autonomous unit of life. And you know, we all know about about DNA and the genetic code and et cetera, et cetera, the important thing to remember is that DNA is a molecule, it's a chemical, and it's lifeless without a cell. It's the cell that brings it to life. It's the cell that enlivens genes by turning them on and off in response to signals and proteins and hormones, but without any of that, you and I wouldn't exist. We would be a lifeless conglomeration of molecules. So I call it the greatest integrating machine. It takes all that genetic code that we possess and animals and plants possess and it integrates them and makes life out of them, and that's what's astonishing about the cell. It's the living unit that integrates all our genetic information and converts it into what we define as life.
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Basu, Narrating: Researchers like Sidd have pushed our understanding of cells further and further. It's allowed us to use cells in ways that, just a few decades ago, we could never have imagined. Think about things like chemotherapy and immunotherapy, blood transfusion and bone marrow transplants, even antibiotics. These are all examples of cellular therapies that are widely used and accepted today.
But that wasn't always the case. Take in-vitro fertilization, for example. When the first IVF-conceived baby was born in 1978, people had a lot of big feelings about it, medically and ethically.
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Mukherjee: IVF was-- it was just considered absolutely absurd. I mean, people thought that, you know, there's-- there's a thousand reasons why you can imagine that that wouldn't be possible and it would be just outside the reach of scientific possibility.
Basu: Yeah, it was outside of people's imagination, certainly. Yeah, yeah.
Mukherjee: Exactly. So there was a huge cry about it. Some people thought that humans have been living with infertility forever, so why is it a disease? And seriously, this was a discussion. Today we know about, sort of, the-- the aching desire for some people to have a baby, they cannot because of whatever reason. And that aching desire is suffering, and so we are, I think in general, not hesitant to call it a real form of suffering. There were moral and ethical questions about quote-unquote "playing God." There were medical questions: what if the child was born with a physical deformity? No one knew. So it was-- As I describe in the book, you know, that first operation was in absolute secrecy, because you could imagine what would've happened had there been, I don't know, a cleft palette or, you know, a defect in blood or some malformed organ.
Basu: It would be held up as the example, right?
Mukherjee: Exactly, and it would be held up as an example of humans trying to play God and having a terrible, terrible outcome. And it's unleashed a whole bunch of other questions. I mean, these questions keep coming back.
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Basu, Narrating: The questions start with: should I choose the gender of my child using embryo selection? That's possible today. But you can see how that quickly kicks down the door to other ideas: actual manipulation of an embryo's DNA with gene therapy. What if I could correct for genetic disorders? If I have cystic fibrosis, for example, can I change the DNA of the embryo to make sure my child won't inherit it? What about blindness or deafness? Or height or weight?
Mukherjee: I pin my North Star in terms of gene therapies and cell therapies where there's tangible suffering. I think that interventions should be linked with disease, not desire. Another way to put them is that they should be linked with what I call emancipation from suffering, as opposed to augmentation of a fantasy or a desire.
Basu, Narrating: But who gets to decide where these lines are drawn?
Mukherjee: There's a gray zone between them, and that's where we really run into some concerns and troubles. Where is suffering? Who is suffering? How does one define suffering?
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Basu, Narrating: Let's take a hypothetical example, at least hypothetical for now. There are people who have extreme short stature. Some say they would like to be taller. Others don't, they say that they're healthy and happy.
Mukherjee: They make a very cogent argument that their lives do not have suffering. In fact, the suffering is inflicted because the world, the environment around them, is not adequately adjusted to their needs.
Basu, Narrating: Meaning a person's height does not inherently cause suffering, it's the world around them that causes the suffering. And if that's the case, should that be what changes, before turning to cellular therapies?
Mukherjee: You know, we would have different chairs in the office. We wouldn't be sitting in this chair, we would have the option of sitting in a smaller chair. These are trivial things we could do to make the environment much more conducive to the many struggles that they have to go through, which are really not struggles, they're-- because we've designed the world for not-- not for them.
Basu, Narrating: Again, we're still talking hypotheticals at this point. But Sidd says it's all within the realm of possibility in the future.
Here's an example that's becoming less hypothetical and more real$% using cellular therapy for treatment-resistant depression. Sidd told us there are trials underway…
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Mukherjee: Starting at Mount Sinai West, Helen Mayberg's works in which she inserts electrodes inside neuro circuits. So, people have called it electroceutical cell therapy. So she puts an electrode inside the brain and stimulates a certain sort of group of cells with electricity, tiny bolts of electricity, for recalcitrant depression. And for a while, the trial was considered maybe a partial success, but more and more they've learned how to really make that trial into a success. It's being tried for OCD, it has a history of being tried for Parkinson's disease and other things.
Basu: Oh, wow!
Basu, Narrating: Another example of a cellular therapy trial has to do with type 1 diabetes.
Basu: You can produce, now, from stem cells, insulin-making cells, and so you're not correcting type 1 diabetes by putting in insulin, which is one way you could do it, or by changing the genes in the pancreatic beta cells that would ultimately help with, you know, restore their ability to produce insulin and not get them dead from from immune attack, which is the usual way that type 1 diabetics become diabetic, but rather, you know, make beta cells that make insulin, grow them up in big quantities in the lab, and infuse them into a patient with type 1 diabetes. You could potentially enclose it in some kind of device so that it would be privileged from immune attack, and you could implant the device. And what's amazing about it is that those cells, because they're integrating machines, and if blood is flowing through them, they can sense, just as your pancreas can sense, when your sugar is high, and secrete insulin by themselves. So they become a pancreas. They become a bio artificial pancreas.
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Basu, Narrating: Cellular therapies are also doing amazing things for people with cancer, like Emily Whitehead who we mentioned earlier. But it comes with a learning curve. See, when Emily was first given the manipulated CAR-T cells, she had an unexpected reaction.
Mukherjee: All her cancer cells started to die, but she had so much cancer in her body that the T-cells went on a rampage almost akin to an autoimmune disease, you know. It was like the body was fighting its own body.
Basu, Narrating: The T-cells caused Emily to go into a profound inflammatory state. She started vomiting, she spiked a high fever, her kidneys were failing. Everyone was terrified that she was going to die. But then they decided to try giving her an anti-inflammatory drug that had just been approved by the FDA.
Mukherjee: They rushed an order to the hospital to get that chemical to be used, in Emily's case for the first time. No one knew it would work or not, and it worked miraculously. It was incredible.
Basu, Narrating: A couple of weeks later, her doctors did a bone marrow biopsy, and she was considered to be in complete remission after that.
Now, because of Emily's case, physicians have much better ways to detect and prevent this type of bad reaction to CAR-T cell therapy before it happens. But there are still limits to what cellular therapies can do…
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Mukherjee: Cellular therapies are being increasingly used to treat cancer. They're very good, these CAR T-cells are very good, at liquid cancers, myeloma, lymphoma, blood cancers, and leukemia as well, but weirdly enough have never been successful in solid tumors. And there's a lot of very intense and very high-level research trying to figure out why not. Something about a solid tumor seems to make these cells not want to kill them. My laboratory has proposed an alternative to that is to use a different kind of cell, not a T-cell but a monocyte, a myeloid cell, that really traffics extremely well into tumors. So we're making those cells into CAR T-cells. We're sort of tricking those cells to behave as if they're like-- T-cell-like, except these are myeloid cells that go into-- And so we've had two, we've had two patients on trial so far, again for solid tumors or solid-like tumors, I would say.
Basu: And how are those trials going?
Mukherjee: Well, I'm not allowed to tell you. First of all, I don't know the answer. And even if I did, I couldn't tell you because the trial regulators would come and-- until the trial's over. Similarly, we have trials going on in India, and, again, very exciting. It's the first time that we have a phase 2B trial for CAR T-cells. We opened one of two, but the one-- the very advanced facility in Bangalore have treated about ten patients, ten kids. And again, I'm not allowed to tell you, but like, all I can say is that we've managed to treat them. You can draw your own conclusions from that.
Basu: [CHUCKLES] Understandable.
Basu: Okay, I'll quit asking you about trials that you really shouldn't be telling more about, or talking more about at this stage. You use the term "new human" in this book quite a bit. What do you mean by that?
Mukherjee: We think about-- you know, we've been sort of conditioned to think about the new human as if the new human is some kind of psychedelic, sci-fi vision of the, you know, future, what I call "Keanu Reeves in a black mumu." But that's not what a new human is. You know, when the first patient was transfused with blood in the earlier part of the century, with matched blood, people really thought that the person who would emerge with another person's blood would be-- is a new human. Louise Brown, when she was born, the first IVF baby, was considered a new human. People undergoing cellular therapy or bone marrow transplant where their bone marrow belongs to someone else and the entire bone marrow is another person's is a new human.
Basu: So the new humans are already here [LAUGHS] in a sense.
Mukherjee: The new humans are already here.
Basu: You know, you talking, framing it in this way, disease versus desire, it just makes me wonder what are the dangers and limitations of constantly trying to optimize the human experience?
Mukherjee: Again, for me, the North Star is suffering, and the word "optimizing" doesn't apply. The word there is "alleviating," "emancipating," whatever it might be. But on the other hand, as you know, there is this-- there's a whole new dialogue that's entered, I think, our conversation about life optimization. I think that it brings a certain disruption in our lives. Life optimization creates the constant anxiety that you are not optimized. I can tell you that I'm very suboptimized in many ways.
Basu: Does that mean underslept, for one?
Mukherjee: [LAUGHS] Well, no, you know, I can give you very particular examples. I lose my direction all the time, I have no sense of direction. You know, I think that that's a trivial thing, but if I was in a forest in a prehistoric age, I'd be dead in a second. I couldn't find my way back to my cave. But all of this said, I think that that optimization, and the exaggeration of choice, creates a constant anxiety that you are suboptimal and you need to be doing more to make yourself optimal. That anxiety's already pervaded our society, that dialogue is already here. Everyone is suboptimal.
Basu: Of course. You know, I wonder if you have-- if I could ask you for two versions of the future, a sort of troubling future of the new human versus a more optimistic future of the new human. What do you see as the possibilities?
Mukherjee: The troubling future of the new human is this life optimization and choice and a slow but steady push towards augmentation, and the removal or the separation and the inability to understand the difference between what I say: disease and desire. And all of a sudden, you know, everyone wants to be a particular way, there's a homogenization of cultures that come with it. There's also a refusal to recognize all that's beautiful and powerful and generative about diversity and human diversity. I don't want to see a world in which everyone looks the same, is the same, behaves the same, eats the same thing, and does the same thing.
Basu: Yeah, yeah. I guess plastic surgery has allowed for that in a very literal sense, but truly, right? A sort of emulation of very similar.
Mukherjee: That's right. There's certain parts of New York where you can go and you can't distinguish one human being from another, so there's that. But on the other hand, you know, the use of cells, understanding-- deepening our understanding of cells can be so important in making us less vulnerable. We just lived through the defining pandemic of our times, COVID, and as I say in the book-- the center of the book is called "A Pandemic." And the reason for that is that cell biology is very, very related to understanding why people get so severely affected by COVID and how to solve it. Vaccines in some ways are fundamentally cell biological tools. So we will hopefully learn to harness more of this cell biology of the immune system to protect against future pandemics, to monitor them in careful ways to protect ourselves against devastating diseases, including infectious diseases and cancer.
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Basu: Mm. Sidd, it's been a pleasure speaking with you. Thank you so much for your time.
Mukherjee: My pleasure too. Thank you.
Basu, Narrating: You can read Siddhartha Mukherjee's book, out now, called "The Song of the Cell: An Exploration of Medicine and the New Human," on Apple Books. You can find a link on our show notes page.
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