We are creeping towards soft immortality: Siddhartha Mukherjee

Interview/Siddhartha Mukherjee

Green thumb: Mukherjee says his only hobby is gardening | Ram Rahman Green thumb: Mukherjee says his only hobby is gardening | Ram Rahman

Q\ This is a quartet. You wrote The Emperor of All Maladies and then The Gene, which you said was a prequel. Is this now a prequel to the prequel?

A\ I call it the life quartet. In some ways, you can call them prequels. But I am sort of mentally ascending the ladder of complexity. At the end of The Gene, you get so much information about genetics. The DNA is this iconic molecule―you see it everywhere; you see it on pages, you see it in advertisements. But you are left with this idea that the gene is lifeless without the cell. It is a molecule and you need the cell to become the unit to decipher that molecule. Without the cell, the gene is a piece of information that has no life.

Without the cell you can’t understand the building of the human body and its pathology. For instance, there is nothing you can’t read the genome and predict―what you and I will look like or potentially what the sources of our diseases are, or even, potentially, how to cure or treat them. You just haven’t had the Morse code of biology. The cell deciphers that Morse code and integrates that Morse code.

Q\ You deal with a metaphysical question in the book, about new humans.

A\ That is the provocative idea in this book. The new human is not going to be a kind of science fictional character. We are already making new humans. The first time someone transfused blood into another person, they imagined very believably that the person would be a different human being. The first time bone marrow transplants were done, there were real philosophical questions raised: are you the same person?

Everyone talks about new humans in a kind of sci-fi way.... The more likely course [is that we] rebuild ourselves by adding and subtracting cells.
Medicine depends so much on systems organisation. All of a sudden, we saw these systems sort of collapse, like a house of cards.
In the US, [cancer treatment] cost comes to a million dollars or more. Our hope is to cut... the whole process down to about 40,000 to 50,000 dollars.

On a very fundamental level, we are dealing with these questions today as we move more and more into cell and gene therapies, where we are replacing cells, changing cells, and ultimately, trying to create a chimera of humans, other parts added to them, etc. I felt that the provocative question I would ask is, why aren’t these new humans?

Everyone talks about new humans in a kind of sci-fi way, as if we were going to become robots. But the more likely course [is] to find ourselves rebuilt, or rebuilding ourselves by adding and subtracting cells, making cells different from ourselves through genetic therapies.

These are humans that have been fundamentally changed. Whether you put a new kidney in me, whether you put a new layer of skin on me, whether you change my knees―some of these are cellular, some of these may not be cellular. But cellular therapy is creating a kind of a human being that we haven’t encountered before―often in which one human’s body fuses with another’s.

When IVF (in vitro fertilisation) was first used, there was a real ethical question and a real conundrum. Because [no one knew] what the baby from IVF would look like. Now, we have become so used to the idea. But, when Louise Brown was born, no one knew that, and there was a real concern―ethical, medical and scientific―that the zygote with sperm in a dish would turn out to be something we had never seen before. Yet, that child is now a fully grown adult and has children of her own. So, again, every time we do this, we are creating new boundaries for who we think we are. Perhaps, we thought that the only way to reproduce was the classical way. But now we know that that is not true. That you can reproduce in a petri dish.

Q\ In this age, you can extend life longer than 100―as it is defined in Hinduism, creeping towards almost immortality. Would you agree?

A\ I would call that soft immortality or incredible longevity. We, with various tools, are slowly creeping towards that. I am talking in the context of where many cancers remain incurable. Heart disease takes 30 to 40 per cent of lives. There are other diseases sweeping across the planet. This book was written just after the Covid pandemic, so it is a very humbling idea.

Extending longevity will be the subject of the last book; it is going to be very much the part of our quest. We will want to extend longevity, but we want to extend longevity with dignity. We just don’t want the husk of a human being just sitting around. But we want the husk of the human being to have vibrance and to have no pain and so forth.

This is where cellular therapy comes in. Once we start this process of regenerative medicine, on ageing people to extend longevity so that they don’t become husks, we begin to create a new kind of human. A human who has been augmented or enhanced to extend life. They may have no overt disease. But their regenerative cells have been uploaded again, or activated.

This is very much a quest within medicine.

[But] it comes with lots of ethical questions.

Should we prioritise that over, for instance, finding cures for deadly diseases? The idea of treating the body not as a unit of healing, but of augmentation is a chilling idea because we have not done that before.

Medicine has not been in the business of augmentation. Most medicine is in the business of treating disease. And is ageing a degenerative disease? Yes. Are we asking the right question? I remind people in the book, when the first IVF baby was born, a lot of people argued that infertility is not a disease.

Q\ I was going to bring that point up.

A\ Because human beings have experienced it for millennia. Some people are infertile, some couples are infertile. And it is an experience of being. But when IVF has come about, we are now routinely thinking about infertility as a disease and offering medical therapy. By the same token, if there is no overt disease, is the lack of longevity a disease? I don’t know the answer. But there has to be a social answer to this.

Q\ You mention the pandemic. It also brought home the idea of mortality among doctors themselves. You have talked about burnout. The pandemic has made it more personal for doctors.

A\ I think that doctors began to realise and get a real sense of how vulnerable our own lives were during the pandemic. But I also began to realise that there are so many aspects of medicine that we don’t know yet. Just as cell biologists began to realise that during the pandemic. It was a time when we went to the hospital and said our own bodies are vulnerable and need protection. In general, doctors have a sense of benign invincibility about them. That was shattered, because doctors and nurses were risking their own bodies, as they went into the hospital.

Medicine depends so much on systems organisation. All of a sudden, we saw these systems sort of collapse, like a house of cards all around us.

Cheering on the champions: Comedian Sarah Silverman (left) applauds to show her gratitude to frontline workers during the pandemic in 2020 | Getty Images Cheering on the champions: Comedian Sarah Silverman (left) applauds to show her gratitude to frontline workers during the pandemic in 2020 | Getty Images

There were many forms of humility that the pandemic created and many forms of uncertainty it created―personal, systemic, organisational, etc. I think there are lessons in all of them. As we now clamber out of this, we are learning those lessons quite deeply. The doctors have burnt out, nurses have burnt out, many have died. Those lessons are being learned in a way that will inform an entire new generation of doctors and nurses.

Q\ You start the book with your friend Sam, the sports writer who was diagnosed with cancer. He asks you to tell the truth. As an oncologist, you must have faced that question a lot of times. How do you tell a patient about loss?

A\I think every individual person’s loss is individual. Some have been preparing for it for months. For some, it comes as a total shock. Some have been reconciling themselves to it over months and years. There is no single templated conversation I have.

I talked a little bit in the book about some things that I generally say. A lot of it is about forgiveness, a lot of it is about reconciliation, and a lot of it is about thinking through what has not been said. There are three pieces of advice that I give people―one is to forgive someone. Tip number two, is to tell someone how much they loved them. The third one is to do something that they have not dared to do before, if they can do it. [It] may be some very small act. In the process, I also take the idea of blaming themselves out, so that they forgive themselves.

Q\ This is what you would expect a pastor to say. Your books have tried to make science human. There is always compassion. How important is that for doctors, that aspect of compassion? How do you keep yourself detached? Is there a possibility of doing that?

A\ Doctors are very attached, if anything. You have to cut a balance between emotional detachment that is required for you to manage a patient.

Three nights ago, I was managing an extraordinarily critically ill patient. You have to find a fine road between being very attached to this patient and having just enough emotional detachment. In other words, being inside the room, but also being outside to figure out exactly what to do. In this person’s case, there were two or three extraordinarily crucial decisions that needed to be made. If they were made the wrong way, the whole thing would have fallen apart.... You are doing this complex balancing act and also trying to get a sense of what the patient feels like. Finally, you are trying to balance that with what the patient wants, in the longer run. Because maybe they will come up with some terrifying disability after this critical incident. Do they want to lead that life with that disability, or do they want to lead the different life?

You are trying to do all of this in the constraints of time―seven minutes―and you can make a crucially bad decision. And change someone’s life forever.

Q\ You have talked about how hard these decisions were when your father was sick. You learnt about being a son as much as a doctor. How do you as a doctor insulate yourself and keep hope alive?

A\ You keep hope alive, because you see what happens when things go the right way. Saving the life of our child with, let us say, leukaemia is totally transformational. It feels that your life will never be the same again. Of course, the child’s life will never be the same again. So that is where the hope, and the hope for the future, comes from. On the other hand, there is disappointment. Also, loss.

Q\ The losses pile up. The pandemic showed that they do.

A\ The losses pile up. The only way that you keep the flame of hope alive is to realise how much meaning those individual cases had for the people who didn’t suffer loss. You have to balance loss against hope. That was one of the crises of the pandemic―so many people lost hope and in losing hope they burnt out. The only way to not burn out is to remind yourselves of the individual lives that were saved, that you help save as a doctor or a nurse. Those lives matter enormously.

Every night in New York, in the middle of the pandemic, people opened their windows and banged dishes in support of the doctors and the nurses. It was one of the most beautiful things that ever happened. I was walking by 166th Street and, all of a sudden, the entire colony was banging their dishes. These are the kinds of things that keep you as a doctor alive.

Q\ In an interview you said that death is not always the worst outcome. Patients sometimes have to come to that point where that is a logical outcome in a way.

A\ I lost two relatives to Covid, and countless other patients I have seen dying in the middle of an unexpected global pandemic. Their loss is very hard to reconcile, because it involves so much. In cancer you go through a process. People often don’t know how complex that process is because it is a bargaining game with a patient and their families.

You have a certain set of chips, and they have a certain set of physiological and personal chips, and they end up going through the process. What you want to do obviously is to treat and cure them and extend their lives. Then you reach a point where you realise that you can’t do that anymore. The conversation turns.

Like wildfire: Mass cremation of Covid-19 victims in Delhi in April 2021 | PTI Like wildfire: Mass cremation of Covid-19 victims in Delhi in April 2021 | PTI

In cancer, especially, palliative care plays an incredibly important role. One of the things that we try to do is involve or work with our palliative care doctors, the nurses who are really professionals in dealing with grief and loss, to try to provide solace. It is highly individualised. For some person, solace might be to tell me, ‘Try as hard as you can.’ For others, to say, ‘I am ready. I have been reconciling myself with this.’ Some people transition between one and the other. They can even transition back. People reconcile themselves and suddenly say, ‘Gosh, I would really like to try something new, try a new trial.’

The idea here as a doctor is to be a reflector, and be a book they can write their words on. I am talking about this metaphorically. Sometimes the words can be very rude: ‘You disappointed as a physician.’ You absorb that. Sometimes the words can be very beautiful: ‘Thank you for helping me through the last stages of my life.’ No loss is identical. It is like dancing your way, with a patient, towards the inevitable loss and inevitable death.

Q\ You trained as a classical singer. But you said you didn’t pursue it because you didn’t feel you had enough grief. Do you think now you have grief or you have to live your life to have the grief?

A\ I am not sure you have to live your life to have grief. You have to understand what it means to transform that grief into music. It’s not just having grief; not everyone who has grief can be a musician. It’s the idea that you have the chance to be able to transform that grief into sound. That transformation isn’t available to everyone. I have learned a little bit more about it. But I certainly don’t perform publicly outside my band, which does sort of a jazz-Indian music fusion. I don’t perform publicly outside that, partly because, again, I couldn’t fathom how to transform that grief into song.

Q\ You write eloquently about depression. Can you talk about living with that? And how do you sort of live with the dark? Or do you have to live with the dark, especially because you are a doctor?

A\ In my case it was triggered by a variety of things that were going on in my life right then after my father’s death. Then a little bit of a hiatus while I was trying to write and then, of course, the mad hit of Covid. All of this came on suddenly, without really any warning. I decided to write about it. And I decided to write about it in the context of cellular therapy and cell. I make no distinction between a patient’s history and my own history. Obviously, there is a genetic component to it, an environmental component to it.

Q\ You have talked about cancer being a big fight that we are going to have in the 21st century. But what about Alzheimer’s? In this longevity, if you can control the mind, you might be able to control everything else.

A\ Some aspects of the mind are now being deciphered. [But] it remains an even greater frontier than cancer. A very prominent neuroscientist once told me that the whole medicine of neurobiology is about 10 to 20 years behind the medicine of cancer. They are trying to figure out as neurobiologists how the mind works and how its pathologies are created. Even today, we have struggled to find even a single drug that is highly effective against Alzheimer’s disease, for instance, or many forms of dementia.

I do think that there will be a new universe that opens up once we begin to open up that black box, but it remains a black box. There are medicines for depression. But they are only marginally effective in most cases.

Q\ You found a link between metabolism and cancer. You call it the fifth pillar.

A\ The link between metabolism and cancer was established a long time ago by Otto Warburg, but was never exploited therapeutically. We launched a research programme in collaboration with Lewis Cantley. Lew is an old friend, a great scientist who discovered the key metabolic enzymes in the body. I mentioned a couple of clinical observations to him, which point to the idea that the patients were getting resistant to a very powerful chemotherapy drug, because it was through insulin.

If we can somehow derail the insulin, we might be able to make that drug more effective. We suddenly realised that there were actually dozens of people in the field who were thinking similarly, who had thought about metabolism as something that had been under-explored.

We launched a consortium at first and then ultimately a company called Faeth, in which we really began to probe the idea of how changing metabolism in all these different ways changed insulin. It is based on precision metabolism, and the trials are ongoing.

Cells and the crab: (From left) Dr Carl H. June, Mukherjee and Dr Arun Anand at an Immuneel summit. Cells and the crab: (From left) Dr Carl H. June, Mukherjee and Dr Arun Anand at an Immuneel summit.

Q\ So by not eating a certain thing…

A\ We have a very precision oriented diet, which is combined with a particular medicine―so that the medicine becomes more effective in the context of the diet. We provide a particular diet which is extremely well controlled. You eat only that diet. We measure your blood, we tell you exactly when to eat it. In some cases, we add another key particular targeted therapy, so that it is precision nutrition.

Q\ Can you talk about what you are doing in Bangalore with the new company and the trial?

A\ We have set up one of India’s first CAR T cell companies. It is called Immuneel. A CAR T cell is a T cell that has been weaponised against cancer. So, T cells are extracted from your own body. Then using gene therapy, we weaponise it to kill cancer cells. We grow them in the lab, and then we put them back into your body. It is a process that can be very highly effective in curing patients, but it is also very dangerous.

Everyone knows that in these trials, some patients will die because their T cells will be highly activated or over-activated and will cause mortality.

We will publish our data in December or January. You will see the incredible progress we have made. There will be great successes and some losses in the trial. Hopefully, we will bring this therapy to India at a fraction of a cost.

Q\ I was going to ask you about costs.

A\ In the United States, typically, if you include the chemotherapy, possibly a transplant, and then finally followed by the medicine, the total cost comes to a million dollars or more. Our hope is to cut that down, not have the transplant, but cut the whole process down to about, let us say, 40,000 to 50,000 dollars, maybe a little bit more. We are really working on trying to make this dream possible for India. We have already transfused 10 patients. We are transfusing about 24. We have a second and third product.