A cell biologist shares the wonder of researching life's most fundamental form

Transcript

TERRY GROSS, HOST:

This is FRESH AIR. I am Terry Gross. COVID has challenged a lot of what researchers thought they knew about how our immune system works. The key to solving COVID's mysteries likely involves a new understanding of cellular science. Cellular science is also leading to tools to fight specific types of cells that have gone rogue or become pathological while, at the same time, not attacking healthy cells. Cancer, HIV, Type 1 diabetes and sickle cell anemia are some of the diseases in which this new approach is being used or is in experimental stages.

My guest, Siddhartha Mukherjee, writes about this new field of cell therapy and what we've learned about the immune system in his new book, "Song Of The Cell" (ph). He's an oncologist, cell biologist and hematologist who treats cancer patients and conducts research in cellular engineering. In the book, he also writes about the period of his profound depression and what he learned about new approaches to electrical brain stimulation that are being tested to treat depression. Mukherjee won a Pulitzer Prize for his book "The Emperor Of All Maladies: A Biography Of Cancer." He's also written about medicine in The New Yorker.

Siddhartha Mukherjee, welcome back to FRESH AIR. I learned so much from your new book. Thanks for coming back to our show.

SIDDHARTHA MUKHERJEE: Oh, thank you for having me, Terry.

GROSS: In the beginning of your book, you write about two cases that reveal how revolutionary cellular modification and engineering can be used in combating disease and how it can backfire. So I want to start with a case in which it backfired. And the patient was a friend of yours named Sam. At least that's the name you use in the book. Would you describe how far his cancer had progressed when he was treated with a cellular therapy?

MUKHERJEE: Yes. Sam's case was a very personal case for me. And I begin the book with it partly to inject a dose of humility right at the beginning of the book. Sam had metastatic melanoma, cancer of melanocytes, skin cells. And it had metastasized to his liver, to his lungs, and to parts of his skin. And he was treated originally with surgical resection. But unfortunately, after the resection, the cancer was detected to be metastatic. And he was then, eventually through - after some initial therapies, put on a novel kind of therapy called immunotherapy.

Immunotherapy is a set of medicines which uncloaks the cancer cells and exposes them to the immune system, particularly to T cells, which are part of the immune system. Normally, cancer cells have found various mechanisms to hide away from the immune system, and that's part of the reason that they can survive and grow. And immunotherapy makes them, to coin a word, re-visible to the immune system and makes the immune system attack them. So that's the good part.

GROSS: What's the bad part?

MUKHERJEE: The bad part is that, unfortunately, when you uncloak any part, any cell in the body, and expose it to the immune system, you also uncloak normal cells in the body. These mechanisms have evolved. These cloaking mechanisms have evolved so that we don't develop autoimmune diseases such as rheumatoid arthritis and other diseases - psoriasis and other diseases. And so when you uncloak the - you know, the tumor, you also uncloak or activate T cells against normal cells. And in Sam's case, it was - he developed an autoimmune hepatitis, which is a very fulminant inflammation of the liver. His T cells began to attack his liver.

So every time - I use the analogy of, you know, animals training on a leash. So we cut off the leash, and they go and attack the tumor. But unfortunately, they also attacked his liver. And every time we would try to kill his tumor cells, which we could, they would - the T cells, these activated - I would - I call them techy T cells, irritated T cells, would also go and attack his liver, causing a very fulminant hepatitis, which we never could control. And that - ultimately, that was what was the cause of death because of this - we couldn't pass through this narrow channel between killing his tumor and killing his normal cells.

GROSS: Now, let's compare that to the case of a 14-year-old girl named Emily Whitehead, who was treated in Philadelphia, where our show is, at the Children's Hospital of Philadelphia, aka CHOP, for a form of leukemia that's cured in 90% of cases and, I guess, kills most of the other 10%. And she was in that 10%. And her trial involved infusing her body with her own T cells, but the T cells were weaponized through gene therapy to recognize and kill her cancer. So what's the difference between the therapy she had and the therapy Sam had?

MUKHERJEE: So in Emily Whitehead's case, it's a different kind of T cell therapy. Unlike Sam - in Sam's case, we give the patient, in this case Sam - we give Sam a drug that uncloaks the immune invisibility of the cancer or activates the T cells so that they can go and attack the cancer. In Emily Whitehead's case, we do something completely different. We extract the T cells from the patient's body. And then, we use a gene therapy to basically weaponize them - to activate them and weaponize them against the cancer. We grow the T cells in flasks in a very, very sterile chamber. And then, ultimately, when the cells have grown and activated, we reinfuse them into the patient's body. So it's sort of gene therapy plus cell therapy given back to a patient.

And in Emily's case - she was about 7, I think, when she was first treated - she had a complete response. She also had a very terrifying course. When the T cells get activated, they release an incredibly inflammatory cascade, sort of like - as I say in the book, it's sort of like soldiers on a rampage. And, you know, you can get so much of a rampage of T cells killing cancer that the body goes a little berserk and can't handle this kind of attack. Now, Emily, fortunately, was treated with a medicine to dampen down that attack so that she ultimately survived. She was the first child treated with this therapy to survive and serves like an icon for this kind of therapy. It's called CAR T therapy. And she still is alive today and applying to colleges, I hear.

GROSS: So just to make sure that we all get this right - so T cells are cells that are activated by the immune system to fight disease.

MUKHERJEE: Correct. T cells are one wing of the immune system. The immune system has multiple kinds of cells. T cells - T comes from thymus because that's the little gland that sits on top of your heart. That way they mature. And, yeah, they're one wing of the immune system. Other wings, you know, would be B cells or monocytes. And other cells are, you know, literally hundreds of cells that create the immune system. T cells are one particular wing of the immune system.

GROSS: And so for Emily, T cells were extracted and reengineered to attack only certain types of cells.

MUKHERJEE: That's correct. Her T cells were extracted and genetically engineered to only attack some types of cells, a very select type of cells, which include the cells of her cancer. Right.

GROSS: So after the T cells were reinfused and the therapy was killing the cancer, but also causing organ failure - and then, the T cell activity was tamped down by a medication. Once all that happened, her recovery sounded like it was sudden and miraculous.

MUKHERJEE: And it - and these recoveries are sudden and miraculous. I've been treating patients in India with variants of these same kinds of T cells. And, Terry, you won't believe how - first of all, how gratifying it is, but also how sudden and miraculous it seems. One day, the cancer is there. The next day, the cancer is virtually gone, eaten up by these T cells. Since Emily's time, we've learned a lot about how to administer these T cells with a much greater degree of safety. Now, still, there still remain deaths from these kinds of - from the overactive - hyperactive syndrome that Emily experienced.

But we've learned to be much, much safer. And there are many mechanisms, many medicines that can tamp down the hyperactive T cell activity so that this CAR T cell has now become, really, a staple in the treatment of certain kinds of leukemias and lymphomas and blood cancers. For reasons we don't really understand, they've never really worked so far in solid tumors like lung cancer and prostate cancer. And we really fully don't understand why T cells can attack blood cancers - like lymphomas and leukemias and myeloma - so much better than they can attack solid tumors.

GROSS: Well, let me reintroduce you here. If you're just joining us, my guest is Siddhartha Mukherjee. He's an oncologist, cell biologist, hematologist and Pulitzer Prize-winning author. His new book is called "Song Of The Cell." We'll be right back. This is FRESH AIR.

(SOUNDBITE OF THE ACORN SONG, "LOW GRAVITY")

GROSS: This is FRESH AIR. Let's get back to my interview with Siddhartha Mukherjee, author of the new book "Song Of The Cell." It's about what scientists have learned about how the immune system functions and about an area of cutting-edge medicine, which involves reengineering cells to use them to fight disease. His book "The Emperor Of All Maladies: A Biography Of Cancer" won a Pulitzer Prize.

There's research being done now to try to direct cells related to immunity to attack only specific types of diseased cells. So how are these engineered cells redesigned to notice specific types of cells that have gone rogue or have become pathological?

MUKHERJEE: There are several angles to this. One angle is to basically find something on a cell, on the surface of a cell - a flag, as it were - that will tell the immune system that it's not part of the normal repertoire of cells. So for instance - just to give you a very simple example - if I was to graft a piece of skin from another - one human being to another, that piece of skin would be rejected. And that's because that - the skin cells have flags on their surface, specific molecules on their surface, which are recognized by T cells.

And T cells go in and say, whoa, whoa, whoa, whoa. Wait a second. You don't belong to this person. And they will reject them. And that's why the skin graft is rejected. So one mechanism by which you can specifically direct the immune system against any cell type is to find such a flag that's in that cell or that cell type and essentially engineer, using a variety of genetically engineering methods - engineer that T cell or make antibodies against that flag, that molecule, that protein that's on the cell surface, and drive the immune system to reject that cell type.

GROSS: You're doing research with a team that's related to creating a type of cell that's never existed in biology. Can you describe what this cell is and why it might prove to be important in combating disease and having the immune system behave in a productive way?

MUKHERJEE: Yeah, it's a very peculiar kind of cell. It's never been - it's never existed in biology. And that's absolutely correct. So if you think about the immune system, it has two very broad wings. And let's talk about those two very broad wings for a second. One broad wing is called the innate immune system. And it's an ancient wing of the immune system. And remember, I talked about the first soldiers that come to battle in an infection. Well, the innate immune system is the first soldier that comes to battle, the first set of soldiers. It has many, many cells that are part of it - macrophages, monocytes, neutrophils and natural killer cells, among other things.

The important thing about the innate immune system is that it doesn't learn, as far as we know. Although, there are some experiments that have started changing this traditional view. But it doesn't know or remember anything about that infection. In other words, if you get that infection again, it will not have any memory of that infection. It'll come again. The battle will start again. The soldiers will arrive again at the same site. There'll be new soldiers. And they will start the battle again. The other part of the other wing of the immune system is called adaptive, adaptive because it has a memory. It adapts to a particular infection. So those cells are - B cells and T cells are examples of that.

And B cells and T cells are unlike the innate immune system in the sense that once you have an infection, they remember. There's a memory compartment. And they remember that you've had the infection. So the next time you have the microbe attack you again, it will remember it and mount an immune response against it. And that's why vaccines work, by the way. Vaccines work because they - you know, they elicit not just antibodies immediately against a virus, but because those antibody-making cells become part of the memory. And they stay inside your body until - and when the virus comes in again, the memory cells are activated. And they may start making the antibody again.

So again, remind - to remind us, innate system and adaptive system. And it's a broad breakage. They are two separate kinds of system. Now, what we've tried to do and we're still trying to do is to take the innate immune system and genetically engineer it to become like the adaptive system, the memory system, so that it carries with it a weaponized - again, using gene therapy, a weaponized way to attack a cancer cell, which has never been done before. These innate cells that we're engineering now carry on their surface receptors that are specific for a cell type or a cancer cell. And what's amazing about them is that they haven't existed before because they're sort of a hybrid between the innate system and the immune system. So these are monocytes that have been reengineered to attack a particular kind of cell.

GROSS: So it would be as if you had already had this kind of cancer and your immune system knew to attack it.

MUKHERJEE: It would - that would be one feature of it, and the other feature of it would be that, for reasons we don't really understand, the - and I told you this before - T cells have been very - CAR T cells, especially engineered T cells, really don't seem to be able to penetrate into solid tumors. They - one of the most chilling images in biology that I've ever seen is a solid tumor where you've - where people have deployed T cell therapies of various kinds. And you can see a rim of T cells surrounding the tumor, but they aren't getting into the tumor.

And we now know some of the reasons why. The tumors make specific factors. They make a specific kind of home for themselves, which is impregnable to T cells. But what's interesting about that home is that they're not impregnable to these neutrophils and monocytes that we're reengineering. They actually - these monocytes go in and out, come in and out without a problem. So what we're doing really is once you arm the monocyte or the neutrophil to be able to kill the T cells, all of a sudden, it goes in. But not only does it go in; it has a weapon. It's been weaponized to kill the T - to kill the cancer cell, pardon me. And so it really is a hybrid, but it's using some natural ability of these monocytes to be able to traffic in and out effortlessly inside solid tumors.

GROSS: Well, can you imagine if this actually worked and became a standard cancer therapy? I mean, that would be remarkable and wonderful. And you would be one of the people responsible for it. So can you talk a little bit about the excitement of working on a project like this and the frustration of not having any immediate answer about whether it's going to work or not? This kind of thing probably takes years, right?

MUKHERJEE: It takes years. And it's a project, I should say, that we're doing in collaboration with another scientist named Ron Vale. And there's a big team in Boston that's carrying out the research. It's hard for me to convey the excitement that's sweeping through the whole field of cell biology. Biology - life sciences in general - has three pillars, incredible pillars - the three basic rules. That means for a long time, physicists would disdain biologists. You know, we were the lesser scientists - you know, the people who brought them coffee. But in the end, perhaps we had the last laugh because physicists are still searching for theories - their general unifying theories.

Biologists have three general unifying theories. The first theory is the theory of evolution, which should be taught in schools, I should say. And the second is cell theory - the fact that all organisms are made out of cells. And the third is the genetic theories - the theory of inheritance in the genetic code and the universality of it across all animals and plants and bacteria. So these three theories are the pillars of biology. And it's - it felt to me that all of these three theories - you know, there're a thousand books on evolution, a thousand books on genetics and very few books on cell biology.

There's all this sweeping excitement because we're now playing with cells. We're making new kinds of cells. We're making - we're putting them into patients' bodies - T cells, pancreatic cells that make insulin for Type 1 diabetes, you know, genetically altered cells to cure sickle cell anemia. That excitement - it's very, very tough for me to explain the kind of - I don't know - kind of headiness, giddiness, the madness, the psychic - I don't know - power that grips you once you get into the field and feel this excitement.

GROSS: Have you, in conjunction with other researchers, developed any therapies that have already succeeded?

MUKHERJEE: The quick answer is maybe.

(LAUGHTER)

GROSS: Quick and definitive answer.

MUKHERJEE: The quick and definitive answer is our laboratory, I should say - I work with a big team - has developed several therapies. They're all in mid-trial. Some of them are in late trials. The ones that are in late trials have proved to be successful thus far. But, you know, there's always a question of how long, how much, etc., etc., etc. But I'm proud to say that I have developed therapies for humans.

GROSS: Can you explain what one of them is?

MUKHERJEE: Well, yes. Among other things, we started a CAR T center of the first kind in India and done what we consider a pivotal trial. We're still in mid-trial, so we are awaiting results, but they've certainly been successes.

GROSS: What is the success? Like, what are you trying to change or cure?

MUKHERJEE: We're trying to change or we're trying to cure, among other things, lymphoblastic leukemia and other blood cancers among them.

GROSS: Let's take another short break here. If you're just joining us, my guest is Siddartha Mukherjee, author of the new book, "Song Of The Cell," about what scientists have learned about the immune system and about an area of cutting-edge medicine which involves reengineering cells to use them to fight disease. His earlier book "The Emperor Of All Maladies: A Biography Of Cancer" won a Pulitzer Prize. We'll be right back after a short break. I'm Terry Gross. And this is FRESH AIR.

(SOUNDBITE OF MUSIC)

GROSS: This is FRESH AIR. I am Terry Gross. Let's get back to my interview with Siddhartha Mukherjee. His new book, "Song Of The Cell," is about an area he says is transforming medicine, the reengineering of cells to fight disease including cancer and HIV. He won a Pulitzer Prize for his book "The Emperor Of All Maladies: A Biography Of Cancer" and has also published articles about medicine in The New Yorker. He's an oncologist, cell biologist and hematologist. In addition to treating patients, he's conducting research into cellular engineering as a treatment for cancer.

There's a personal chapter that relates to medicine in your new book. And that's a chapter about depression, which became a special interest of yours in 2017 after your father died when you sunk into a very profound depression. And antidepressants helped, but only moderately. And you spoke to a researcher about depression, and he described depression as a slow brain problem. What did he mean?

MUKHERJEE: Well, the brain is made up of cells. Brain - made up of neurons, nerve cells. And for the longest time, people thought that - the way the neurons communicate with each other is through chemicals. They secrete chemicals into a tiny, little space between neurons, and they talk to each other through those chemicals. Now, for the longest time, researchers thought that a particular chemical called serotonin was low or missing in the brain. And if you just up the level of serotonin, essentially like, you know, increasing the seasoning in a soup, you would allow that the neurons that are responsible for depression, or the nerve circuits that are responsible for depression, to be reset, and everything would be fine again.

But that's not what generally turned out to be the case. First of all, if that was the case, you'd react to an antidepressant like a serotonin uptake inhibitor. So these are drugs that increase the level of serotonin. You'd respond to that instantly, but you don't. So Paul Greengard had a different hypothesis and has, you know, continued to have a different hypothesis. Unfortunately, he died.

But his hypothesis was that it's not just seasoning in the soup. It's not just the amount of serotonin. It's what serotonin does to the next cell, in fact, that these chemicals make profound biochemical, metabolic and other changes in the second cell, in the cell that's listening, that is responsible not only for normal physiology, but for diseases like depression. And that's called a - he called it the slow pathway because it doesn't - it's not just sort of the quick chatter between neurons, but a much slower pathway that takes place over maybe, you know, minutes, seconds, perhaps days and perhaps weeks to change.

GROSS: And so that slow pathway translates to depression?

MUKHERJEE: Greengard believed that that slow pathway was responsible for depression. And that's why these serotonin inhibitors - uptake inhibitors - sorry - which increase the level of serotonin, don't work instantly. You have to make very slow changes in cells - change their physiology, change their metabolism, change their biochemistry, change the proteins that they're making - in order to change the neural circuits that are responsible for depression. So that's why he believed that it was the slow pathway. And in fact, he'd found some very promising evidence that it was the - some precise proteins involved in this slow pathway that are responsible for depression.

GROSS: Where do other scientists stand on this theory?

MUKHERJEE: People are beginning to believe this theory more and more. Earlier, Greengard had shown - for which he won the Nobel Prize, Greengard had shown that there are aspects of this slow pathway that are responsible for responding to other chemicals, like dopamine, that change, again, the communication between neurons. And he was just about extending - so, you know, he'd discovered that this was relevant in Parkinson's disease and schizophrenia. And he was just about extending this work to depression when he unfortunately passed away.

GROSS: When you were going through the period of depression, did it cause you to lose interest in your research or in your patients?

MUKHERJEE: It didn't cause me to - I would say superficially no, in the sense that I could certainly continue the actions. But there was something missing. I could sense - very much get the sense of that - what was missing. One of the things that went missing was the sense of connection both to my research and to my patients. I've always been very connected to both. But I could see that connection fading away. And in fact, that's when I started taking action and really started to go and see, you know, a talk therapist and change medicines and really work hard on my brain. You know, exercise is one of the best antidepressants that there can be - you know, seasonal changes. I tried everything. And as I said, maybe it was a slow pathway, but it slowly abated.

GROSS: Illness can create depression or exacerbate it. Do you feel like going through a period of depression yourself helped you understand what some of your patients are experiencing?

MUKHERJEE: Oh, absolutely. I could sense the - you know, the sense of doom and also the sense of uncertainty. Uncertainty itself causes anxiety, which is actually one of the most prominent symptoms of depression. Often, people will come and tell you, I'm extraordinarily anxious. But in fact, what's going on with them is that there's an underlying depressive component to this. The anxiety is a manifestation of that. It's the manifestation of a mood disorder rather than some kind of particular panic that's going on through their brain.

And I think, you know, illness causes one of the most profound forms of anxiety that we know. And so I very much encourage particularly cancer patients to seek out psychiatric help, talk therapy, medicines, if needed, and any kind of therapy that will help them because it let me - my own experience with my mood and my mood disorder allowed me to really understand what patients go through.

GROSS: Let me reintroduce you here. If you're just joining us, my guest is Siddhartha Mukherjee. He's an oncologist, cell biologist, hematologist and Pulitzer Prize-winning author. His new book is called "Song Of The Cell." We'll be right back. This is FRESH AIR.

(SOUNDBITE OF PAQUITO D'RIVERA'S "CONTRADANZA")

GROSS: This is FRESH AIR. Let's get back to my interview with Siddhartha Mukherjee, author of the new book "Song Of The Cell." It's about what scientists have learned so far about how the immune system works and about an area of cutting-edge medicine which involves reengineering cells to use them to fight disease. His earlier book "The Emperor Of All Maladies: A Biography Of Cancer" won a Pulitzer Prize.

There's something, a phenomenon, that researchers face called the sand-in-the-eye problem. And that is, like, when you're doing research on, like, a new medication or a new treatment, like, everything is coming up the way you want it to - it's all checking out - except there is this one thing that does not fit the pattern and that contradicts the pattern. Have you come across that yourself in your research? And if so, like, how do you deal with that, when everything's falling into place, but this one thing seems to disprove everything else?

MUKHERJEE: Yes. Just thinking aloud, as you say, as you speak - I'll give you a great example, actually. Our laboratory discovered, along with another laboratory at exactly the same time - discovered cells in the skeleton that are stem cells. For a long time, people believed that bone was static and you can't - as adults, you couldn't make any more bone or cartilage. And we discovered a stem cell that sits inside a particular part of bone, which can give rise to bone and cartilage even during adulthood although their numbers drop.

So we wrote this very nice and fancy grant saying that, you know, in - when cartilage degenerates in osteoarthritis - big disease, a very common disease neglected disease in - particularly in - because it's in women. We wrote this grant very proudly saying that, you know, our hypothesis was that in osteoarthritis, these cells would rise up like phoenixes from the ashes and start regenerating very actively. And they would, you know, regenerate the cartilage and thereby cure the disease. And shock and surprise, we found exactly the opposite. We found that when we looked at the actual tissues when we caused injuries, these were the first cells to die.

And so we started forming a completely new idea or theory about osteoarthritis, which involves the death of these stem cells, and realized that maybe - and this is a hypothesis, again - maybe osteoarthritis is a stem cell disease. This is a stem cell problem. And that was a sand-in-the-eye problem because we had always expected just the opposite and found something completely different. And many of the other facts wouldn't fit until we had found this peculiar surprise. And of course, our grant was given, but we had to sheepishly write back and say, actually, we found just the opposite.

GROSS: But still, it led you to a revelation.

MUKHERJEE: Well, that's how science works. I mean, you know...

GROSS: But an unfunded revelation.

(LAUGHTER)

GROSS: You know, now you need a separate funding to pursue the new revelation.

MUKHERJEE: That's right. That's right. Well, that's - it's important to know what the - it's important to convey that that's how science works. I mean, there's a famous Keynes - attributed to Keynes at least - saying that, you know, when facts change, I change my mind; what do you do, sir? You know, this goes back to this very uncertain time that we had around the pandemic when things seemed to change. And there was this big anti-science sentiment that kept saying, oh, you know, scientists are egghead idiots because they keep changing their minds. But we keep changing our minds because we retain the luxury, or the prerogative, to change our minds when facts change.

And in the pandemic, facts kept changing. And so it wasn't - it was uncertainty. There's a difference between uncertainty and authority. Uncertainty is not knowing something. Authority is claiming something - or a false authority is claiming something even when you don't know it. And I think that those are two different things. And part of the anti-science sentiment that swept through the United States during the pandemic was because of the confusion between uncertainty and false authority or authority. There were many uncertainties, and they kept changing.

And that's part of the reason that, you know, the CDC changed. The FDA changed. We had to - you know, we had to adapt to multiple changes at multiple times. I'm not saying they were always right. They could have - they were sometimes wrong. They were sometimes right. But what I am saying is that the scientific process - leave the FDA aside. Leave the CDC aside. The scientific process had to be maintained and was maintained throughout the pandemic.

GROSS: You're an oncologist. What is one of the questions about cancer you'd most like to know the answer to?

MUKHERJEE: I'm very interested in cancer metabolism. I'm interested in how cancers attract or take up metabolites - metabolites are things you eat, essentially fuel for the cell - and how it changes and differs from a normal cell to a cancer cell. We know that they're different. We know that normal cells have different metabolic requirements compared to cancer cells. And in fact, one of the big efforts in my laboratory, along with several other laboratories, is to see if those could be used, those vulnerabilities, those changes could be used to target to make a new kind of cancer diets, diets that would specifically inhibit or target cancer cells - really imagining diet as a kind of therapy.

GROSS: So much of your writing is about medicine and breakthroughs and what scientists are learning. One of the very personal pieces that you wrote that was published in The New Yorker was about your father's declining health and then his death. And your father was - you're originally from Delhi, and your father was living in Delhi when he was dying. And, you know, so when you knew that things had really taken a turn, you got on a flight as soon as you could to Delhi.

And, you know, he was in the hospital at this time. And you write about the indignities, the mistakes on the part of the medical team, the faulty equipment, the deteriorating conditions in the hospital, that your father was up against and that horrified you. But I'm wondering if you've seen similar problems in American hospitals 'cause American hospitals are old. They appear, at least on the surface, to be very dirty. Often, there are mistakes that are made.

MUKHERJEE: So all of those are true, I think. I think that there's been a great - this is - I've noticed it particularly after COVID. I think there was a great degree of doctor and nurse burnout during the COVID pandemic. And I've been involved with many efforts to prevent - try to prevent that burnout. A lot of it has to do with excessive paperwork, excessive work put on doctors. It's been building up over generations, really. You know, we've converted doctors from thinkers into form fillers and nurses from caregivers also into form fillers. You know, I'm very keen to find a way to sort of declare 2020 the year of the nurse. There was this very moving moment in New York when people would open their windows at 6 p.m. in the evening - I don't know if it was true in Philadelphia as well, but - and bang pots. It was really - brought me to tears for all the frontline health care workers, nurses, janitors, health care cleaners, you know, the folks who wash scrubs and so forth.

I think that a lot of this has been exacerbated by physician burnout and nurse and health care worker burnout such that our hospitals are now prone to looking worse, having less equipment, having equipment that can't come on time. Today I read in the newspaper there's a shortage of mental health drugs. There has been shortages of - you know, there have been times that there have been shortages of, you know, very essential medicines, chemotherapies that we can't get. So I think that the malaise pervades the medical system. It's not specific to one country. It's specific - it's all around the world. And it's been exacerbated by COVID.

GROSS: Well, let's take another break here. If you're just joining us, my guest is Siddartha Mukherjee. His new book is called "Song Of The Cell." We'll be right back. This is FRESH AIR.

(SOUNDBITE OF YO LA TENGO'S "WEATHER SHY")

GROSS: This is FRESH AIR. Let's get back to my interview with Siddartha Mukherjee, author of the new book "Song Of The Cell," about what scientists are learning about how the immune system functions and about an area of cutting-edge medicine which involves re-engineering cells to use them to fight disease. His earlier book, "The Emperor Of All Maladies: A Biography Of Cancer," won a Pulitzer Prize.

Can I ask, having seen a lot of patients who have cancer go into decline and then die, what was it like seeing your own father, who did not have cancer but did go into decline and die and - you know, the decline took place over an extended period. But you kept seeing signs of further decline, knowing that he probably wouldn't be able to get out of that downward cycle. What was the difference for you, seeing it in your own father and seeing it in your patients?

MUKHERJEE: Well, the difference, I think, is that when it's personal, when it's your own father, when it's your own family member, you begin to live in the limbo of uncertainty that patients live in. And you as a doctor - you can sense it. But you sense it in second person, as it were - as a child, as a son. You experience it in first person. And it's a very different kind of feeling because the uncertainty is about making what I would call critical micro-decisions, extremely anxiety-producing, critical micro-decisions. Should we move him from this room to that room? Now, under normal circumstances, when I'm a doctor, I can be - quickly I can make that decision. When I was a son, I found myself totally paralyzed about these sort of, you know, micro-uncertainties.

And then the second thing was sort of when to stop because - and I know Atul Gawande has written very movingly about this. But the question of when to stop - because you have a patient, and there's a glimmer. You know, there's a tiny glimmer. He turns his face towards you when you talk to him. But is that just a coincidence, or is that a sign of something - you know, his brain coming alive again? And the next day, it doesn't exist. And the third day, it comes back. And you don't know. You don't know what decision to make next. And that's just really, really, really difficult.

GROSS: How did you and your mother decide when to stop treatment?

MUKHERJEE: Well, there was a point of time when it became clear that if he were to ever come out of what - he had a bleed in his brain. And if he were to ever come out, he would never be the same again. And my father was very clear about his wishes. That's very important, by the way - is I ask patients when they are at the best of - you know, the best of the health that they can be in to be very clear with themselves and their families about their wishes and to actually have that conversation, if possible, in front of me so that I know and they know and their families know what their wishes are. How would they like to be alive? And some people say, look. You know, I want to be alive at all costs to see my grandson's wedding. Even if I have to be in a wheelchair and half slumped over, I want to be there. Some people say, I don't want that life. I'm done. You know, I'm done.

My father was very clear. He did not want to be in a particular state. He did not want to be bedbound. He was a natural traveler. You know, he loved wandering around. In fact, it was his wandering around that ultimately caused him to fall and have a head bleed. But he loved wandering around. He just didn't want to be confined. And so once we realized that he would spend probably the rest of his life in some kind of confinement, you know, there was a very moving moment when he was totally, you know, not fully conscious. And the nurse came to change his clothes. And he - the only word he would say is no. And that's when I knew that that we had to stop.

GROSS: Like I mentioned, that piece you wrote about your father was so moving. In preparing my interview with you, I thought, I'm going to read some of your medical research and see what that is like. And I - because you have a list of your articles on your website. And I looked at the articles and realized I hardly recognized any of the words in the titles of the articles.

(LAUGHTER)

GROSS: So I thought, OK, I won't read these. But, you know, you write in two really opposite directions. You're a beautiful, elegant writer, even in your books about medicine that aren't personal in the way the piece about your father is. The metaphors and descriptions you come up with are so, like, easy to follow. And, you know, it's just, like, beautifully written. But in the science papers, that's just kind of, you know, a language that only scientists understand. I'd like you to talk about those two different kinds of writing. I don't think many people can pull off both ends of it.

MUKHERJEE: Well, so they are very different kinds of writing, but they have one similarity, which is I like to write what I call pared to the bone. I like to write close to the bone. And by that, I mean that in a scientific article that I'm writing or journal article I'm writing, I try to squeeze out any excess words, any excess distraction so that you can focus on the point. Now, in my books, in my essays, etc., it's a very different kind of writing. It has to be more colorful, more vivid in some ways, use much more - use layman's language, not even much more - use layman's language. But again, I'm trying to write to the bone, which is to say I'm trying to get to the essence of what's true.

And often - you know, often people will critique it and say, well, what about - you know, why didn't you add X or Y or that person's name or this person's contribution? And I'll say, well, it's because I'm trying to get to the absolute essence of what's being - I'm trying to extract out in - even in my so-called literary writing, I'm trying to extract out things that are absolutely essential to that. And everything else in my books has moved to the footnotes. So I often tell people, if you really want to read the book, you might read a footnote. And sometimes my footnotes are, you know, a page and a half long. So I think there's similarities, but they're also very different forms of writing.

GROSS: Yeah. You got a lot of long footnotes in the new book.

MUKHERJEE: Yes.

(LAUGHTER)

GROSS: You know, in the book, you refer to the excitement of the first time you looked at a cell under a microscope. Would you describe that moment and why it was so exciting?

MUKHERJEE: I had seen cells before to some extent because I was working with - you know, as an undergraduate, I worked with yeast and other cells. But they were fleeting times. But this was the first time that I really cultured a cell. This was, in some ways, my cell. Of course, it wasn't my cell. It was a cell of a mouse. But it was a cell that I had grown in a petri dish. And this happened to be a T cell, an immune cell.

It's a kind of astonishing feeling because you suddenly realize that you're looking at the basic fundamental unit of life and that this blob that you're seeing under the microscope, sort of this glimmering, refulgent blob of a cell is the basic unit that connects us and plants and bacteria and archaea and all these other, you know, genera and taxa across the entire animal and plant kingdoms and that we are made up of these things, that if I were to train my microscope on my skin, I would find them. You know, on my brain, I would find them. And it was incredible because also while I looked at it, the T cell moved, and then I could sense the sense that - sort of the pulse of life moving through it. And that was just something quite incredible.

GROSS: Siddhartha Mukherjee, thank you so much for talking with us, and congratulations on your new book.

MUKHERJEE: Thank you very much. And thank you for having me, Terry.

GROSS: Siddhartha Mukherjee is the author of the new book "The Song Of The Cell." Tomorrow on FRESH AIR, author and LA Times columnist Steve Lopez confronts a tough question - should he retire? In his new book, he puts on his journalist's hat to tackle the question. He talks to geriatric experts to people who've quit working and love it and ageless wonders like Mel Brooks and Norman Lear, who apparently never will quit. I hope you'll join us.

(SOUNDBITE OF EKAYA AND ABDULLAH IBRAHIM'S "THE MOUNTAIN OF THE NIGHT")

GROSS: FRESH AIR's executive producer is Danny Miller. Our technical director and engineer is Audrey Bentham, with additional engineering today from Tina Callique (ph). Our interviews and reviews are produced and edited by Amy Salit, Phyllis Myers, Sam Briger, Lauren Krenzel, Heidi Saman, Therese Madden, Ann Marie Baldonado, Thea Chaloner, Seth Kelley and Susan Nyakundi. Our digital media producer is Molly Seavy-Nesper. Roberta Shorrock directs the show. I'm Terry Gross.

(SOUNDBITE OF EKAYA AND ABDULLAH IBRAHIM'S "THE MOUNTAIN OF THE NIGHT") Transcript provided by NPR, Copyright NPR.