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Siddhartha Mukherjee: Cell biology is like a thousand flowers blooming

Author Pranay Lal interviews cancer researcher Siddhartha Mukherjee about his latest book, the future of the covid-19 pandemic and the human body, and the debate around cancer vaccines

Cancer researcher Siddhartha Mukherjee and (left) author Pranay Lal. (Photo by Pradeep Gaur)

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Anti-science” is a word that came up a lot when Lounge facilitated a conversation between Indian-American cancer physician and researcher Siddhartha Mukherjee and biochemist and author Pranay Lal earlier this week. Misconceptions around the use of hand sanitisers, ridiculous theories on 5G mobile networks, and the coronavirus—the covid-19 “infodemic” is as big as the actual pandemic. When this misinformation is coupled with the vast reach of social media, panic ensues. After a point, it becomes difficult to ascertain the veracity of such information. Recent studies have also indicated that false information regarding health issues leads to a probable threat to public health.

Lal, who works in the areas of environment and public health, has an innate love for the natural world and the life forms it supports. His two books, Indica: A Deep Natural History Of The Indian Subcontinent (2016) and Invisible Empire: The Natural History Of Viruses (2021), are testament to that. Mukherjee uses science storytelling as art to show the human aspect of things that are so technical at times. He has three books to his name—the Pulitzer-winning The Emperor of All Maladies: A Biography Of Cancer (2010), The Gene: An Intimate History (2016) and his latest, The Song Of The Cell: An Exploration Of Medicine And The New Human, which explores the human body’s smallest unit—the cell.

The two award-winning scientist-authors had not met before but they quickly struck up an easy rapport, arising from their curiosity and mutual respect for each other’s work. “I want to talk a little about the book but how do you see the future?” Lal asked Mukherjee as they set the tone for the chat.

The conversation flowed easily as they shared their concerns and opinions about the state of science, research and politics, and swapped notes on writing, their love for fiction and non-fiction, and the influences on their work. What made the conversation more special was the fact that both share an alma mater, the University of Oxford.

It’s an interesting time in the world of science and medicine. On the one hand, the biomedical sector is inching closer to finding medical breakthroughs, in the form of vaccines, for diseases such as malaria. New innovations are being tested in vaccine development and deployment for other diseases as well. But on the other hand, misinformation, fake news and incomplete scientific information, often with damaging consequences, have never been at such a peak as witnessed during the ongoing covid-19 pandemic.

Mukherjee and Lal traced the former’s route to the world of cancer research, which started with working with the likes of American biochemist and Nobel laureate Paul Berg, whom Mukherjee now counts as a close friend, and then with Alain Townsend, the renowned professor of medical immunology at Oxford University, and Connie Cepko, the Bullard Professor of Genetics and Neuroscience at Harvard Medical School. They also looked to the future and discussed the ever-changing paradigm of science, the possible gaps in cancer prevention, the growing chatter around cancer vaccines, the double-edged sword of herd immunity, and how the SARS-CoV-2 virus could evolve.

The last bits are increasingly relevant today as we see a surge of covid-19 cases in China, where the outbreak of the novel coronavirus was first identified almost four years ago. A lot has changed since then. As Mukherjee explains, the world was underprepared for a pandemic of this magnitude. While vaccines have helped, he believes the Western world needs to work much more closely with other countries to prevent—or at least be better prepared for—future disease outbreaks.

Vaccine inequality has had a big impact on the economic fallout of the pandemic, apart from the loss of life. The natural world and the human body have become so closely intertwined that there is now no scope for the world to repeat the mistakes of the past. In a recent article for Lounge, Lal argued that the next pathogen waiting in the wings will be all of our making: “We need answers to many more questions before we can lay out even a framework to predict the next outbreak,” he wrote.

At a time when people are still struggling to understand the complexities of the ongoing pandemic, listening to these two scientifically sound and reasonable voices is an important start.

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Edited excerpts from Pranay Lal's interview with Siddhartha Mukherjee

Pranay Lal: I want to take you back to your college days. You started with Paul Berg at Stanford. You couldn’t have asked for a better foundation at a time when recombinant DNA technology was booming and you were in the best lab. Your next move was to Oxford, to Alain Townsend’s lab, who studied expression of peptides as tags on cell surface, which T cells could detect. And finally, at Harvard, you worked with Connie Cepko, where you made sense of how the human genome makes us who we are. And I think that’s where you understood the interplay of gene, genome and cell. It was perhaps a full cycle for you. Tell me about that journey. Would I be wrong in saying that you wrote about cancer first, then the gene and then the cell, though they should be read in the order of ‘The Gene’, ‘Song Of The Cell’ and then ‘The Emperor Of All Maladies’?

Siddhartha Mukherjee: That’s why we say actually it’s a little bit like Star Wars. There’s sort of, like, prequels to sequels to prequels.... One way to read the books is to read The Gene first, then read The Song Of The Cell and then read The Emperor Of All Maladies, which follows my own journey.

But my journey into writing them was somehow the opposite. The most immediate was Emperor because I was in the cancer wards, then became interested in cancer genetics and cancer genomics. Our laboratory did a lot of work on that. And then cell biology—as I became a more mature investigator, I realised that my field is really stem cell biology and immunology. I own 50-60 patents and have started multiple startups. They are startups because that’s the only way to make medicine come alive, as it were. But really, the foundational technology was often a basic discovery made in the laboratory. So, yes, there are two ways to read these books. One of them is ascending the ladder of complexity, as you say. And the completely different way is to read them as they were written.

In structure, I find this book slightly different from your earlier works. Why is it that you chose to break this down into different cell types, while earlier you went into a single narrative?

Well, because that’s what the book demanded.... In the case of Emperor, it was very easy because there’s a kind of a hunt: hunt for a cure, hunt for treatment, hunt for prevention. There’s a chronological way you can describe that because that knowledge is built on one piece of knowledge built on another.... In Gene, similarly, you could take a chronological view of our deepening understanding of genetics.

When you come to Cell, it becomes much more complicated. There’s a historical prologue, which is relatively chronological as scientists (Antonie van Leeuwenhoek) begin to look down the microscope and discover the cell; (Matthias) Schleiden and (Theodor) Schwann create cell theory and work on how to extend cell theory into cellular pathology.

But if you think about the world of cell biology, it’s like a thousand flowers blooming. There are people who go off and work on the immune system. Other scientists are working on embryology and others on the structural and functional anatomy of cells, and homeostasis—the many dozens of properties of life, each of which is illuminated by cells and cell biology. And so, this book becomes, if you want to compare it within the world of fiction, a series of linked short stories. Each one is complete on its own. And yet, you meet that same character later in this linked short story sort of way.

It’s a very unique structure, it’s a very challenging structure in terms of writing it. But it’s the only one that would work. It’s like patchwork, a quilt work. If you put the quilt together without this organising principle of each sub-property of life being illuminated or emerging from the cell, it would be a big khichdi. The readers would get confused and certainly I would get confused.

You have said earlier that your wife reads your early draft. Then you have two sets of people who read it: the detractors and the others who say yes, keep going. But who do you test your structure with?

It’s an internal process. The mapping of a book takes the longest time before the book is written. The mapping of the structure of a book is putting the skeleton together and you can then hang the body, the tissues on the skeleton, but you need the skeleton first. Usually, I sketch it out. You have to see it visually—how the book is going to be structured. In Gene, I made a timeline which is very important. But with Cell, you couldn’t make such a timeline easily because so many things happen at the same point of time.

Siddhartha Mukherjee's latest book, 'The Song Of The Cell: An Exploration Of Medicine And The New Human, explores the human body’s smallest unit — the cell.
Siddhartha Mukherjee's latest book, 'The Song Of The Cell: An Exploration Of Medicine And The New Human, explores the human body’s smallest unit — the cell. (Photo by Pradeep Gaur)

I know that you read a lot of fiction. I don’t read any fiction at all. I know you read Jennifer Egan. When you say a patchwork of stories, who do you have in mind?

It’s funny that you mentioned Jennifer Egan. Egan also sometimes writes a patchwork of stories.... Raymond Carver has a similar structure as a patchwork of stories. There are film-makers who have done this many times: Robert Altman, who made Short Cuts, for instance.

I want to talk about another term you use quite well—“sobering”— when you talk about our fight against cancer. I have seen it in interviews you have done over the past seven-eight years. When you are asked questions about your assessment of cancer research, you say it’s sobering. Could you expand on that?

Cancer is a genetic disease. Obviously, there are environmental features that ultimately cause genetic changes. Those genetic changes then create several abnormalities in the cancer cell. It is a genetic disease in the sense that genes are being either activated or inactivated.

There was a feeling in the cancer community that once we solved the cancer genome through projects like the Cancer Genome Atlas, much of the physiology of cancer would fall out of that. And that therapies, particularly personalised therapies, would fall out of that effort in the early 2000s. When I use the word sobering, it captures the idea that it didn’t happen, and is yet to happen. There’s certainly a lot of progress. This is not to deny the importance of the Cancer Genome Atlas. But it has been sobering because it’s not as if 15,000 new therapies have popped out. Each one of the new therapies for cancer, particularly effective ones, has had to be dug out of cold hard earth, often using the cell biology of cancer, which is not something that has come out of the Cancer Genome Atlas. To find the cell biology of cancer requires a kind of deep journey into cancer.

What is the kind of breakthrough we are waiting for? We have results from the Human Genome Project, we have whole genome sequencing, we have new sequencing technologies. Where do you think the gap is? Is the gap in technology or is it in imagination?

I think the gap always begins in imagination and then becomes a gap in technology. The imagination is changing more towards, what I would call, micro environmental, immunological ways to attack cancer. There will be another phase. I don’t know what that phase is going to be. It may have something to do with killing cancer using different mechanisms that are not just standard cytotoxic mechanisms. We need a lot more imagination around cancer. And a lot more imagination on cancer prevention.

One of the things you emphasised earlier was the breakthrough with the HPV vaccine. There was hope that we will have more cancer vaccines. What do you see as the future of cancer vaccines?

A vaccine depends on finding something that’s activating the immune system against a foreign body. The problem with cancer is that it’s very hard to find things that are foreign that a vaccine will recognise. Now, HPV is very different, because it’s a virus that causes cancer. There are certain viruses that do cause cancer but many cancers are not caused by viruses. HPV being an exception, it is a successful programme in preventing cervical cancer, where it’s deployed properly. It counts as an enormous breakthrough in cancer research. Cervical cancer, and to some extent, head and neck cancer should become preventable diseases with the appropriate deployment of the vaccine.

I find it a little bit hard to convince myself that there will be a cancer vaccine for non-viral cancers, because it’s going to be a tough slog to find elements in the cancer that are unique and different, and are not present in other parts of the body.

I am a little worried about the rhetoric... because of the success of recent vaccinations against various viruses, including against covid. I am a little worried that this cancer vaccine drumbeat has started.

What about HIV?

HIV, of course, is linked to several cancers. Most of those cancers arise, we now know, not because of HIV itself but because it paralyses the immune system. Most cancers, not all, that arise in the context of HIV are cancers where there’s a viral link. Kaposi’s sarcoma virus is a great example, which is part of the herpes virus family and causes Kaposi’s sarcoma... Now, if I am understanding it: Your question is why don’t we have an HIV vaccine?

It was well funded. Several large foundations put in money...

We know the answer to some extent… because HIV is a unique virus that mutates extremely rapidly, certainly more rapidly than SARS-CoV-2, which causes covid. It mutates so rapidly that even in a single person you may have multiple strains of HIV. We know this very well from sequencing. That’s a very big challenge for a vaccine because even in a single person, it’s a virus with a thousand faces. That said, there are parts of HIV which we are now recognising and there’s a new generation of HIV vaccines emerging that may be much more promising than the first generation.

The reason I asked is because in the early 2000s, HIV vaccine design, using the adenovirus vectors and others, was largely to look at whether that template could be used for making viable cancer vaccines. Are we abandoning that?

One question has to do with the vaccine platforms. You can make various platforms of vaccines, AV and mRNA being some of them. A platform is a technology by which the vaccine delivery happens. What the vaccine is against is a separate question. You can mix and match that. The platforms keep evolving: adenoviral vectors, adenovectors, mRNA, and so forth. The problem with making vaccines, cancer or HIV, has not shifted: You might invent 50,000 platforms but until you find a viable targetable mechanism, and a targetable target in either HIV or cancer, you are going to be stuck with a platform without a vaccine.

A mural depicting the pandemic in Delhi. Work on pandemic prevention is an evolving field, says Mukhjeree.
A mural depicting the pandemic in Delhi. Work on pandemic prevention is an evolving field, says Mukhjeree. (Getty)

Let’s come to the pandemic. Your Twitter handle was one of the most followed. You were one of the few sane voices at the time. You have said that we might be living in an age of anti-science. Are people dropping off vaccination programmes because the variants are slightly more benign? And if so, what are the dangers from this?

Like all science, it’s an evolving paradigm. In the US, there are anti-vaxxers, then there are people who are just exhausted of being vaccinated. There are people, who I think are reasonable voices, who are looking at the risks and benefits of vaccines in different subpopulations. That risk benefit analysis is a reasonable analysis to do.

It’s a constantly evolving field. Tomorrow we might have a highly pathogenic variant of the virus. In which case we will have to go back to getting revaccinated. Or it may be that the virus becomes progressively more attenuated. There’s a lot of herd immunity still left over from the vaccines that were originally given or the people infected with Omicron.

There is a chance that if there is not another highly pathogenic strain of the virus, we may have an annual covid vaccine or perhaps one that covers most of the strains as they come along. It’s important to follow rational voices in all of this. But you can only follow those rational voices if you understand that this is a process that’s constantly changing.

Given that herd immunity might be problematic, because that’s also going to change every year with all the new strains, do you think there is a possibility of inoculating the population of a country, say, through herd immunity?

It would be the last of my choices. I think the paradigm that’s worked for influenza is likely to work for covid, which is constant surveillance, including immuno surveillance, particularly from hot spot zones, followed by containment. The world was grossly unprepared for all of this and there were mistakes made all along the way. I think it would be a real tragedy if we repeated them.

What do you think have been the corrective steps so far?

Now there’s large sequencing efforts, much more surveillance as long as the data is provided. There is hot spot identification, sequencing of mutations and variants, understanding of immunity and cross-immunity. My own lab published one of the first papers on vaccine breakthrough infections in the context of Delta. We are going to publish another data set in the context of Omicron now. This is the Bahrain data set, which is very detailed, because they have every single person’s data, and we analysed it with the help of lots of people. There’s more preparedness in terms of the stocking of not only medication but also oxygen. Then preventative things like N95 masks and other strategies that can help front-line workers protect themselves, should another pathogenic wave sweep through the world.

What you mentioned is largely the biomedical part of it. I am worried about institutions. I wrote quite vociferously about covid, saying that the excessive use of sanitisers is a stupid idea. But it’s still there. The World Health Organisation (WHO) website has it, the US’ Centers for Disease Control and Prevention has it, the Indian government has it. You know it’s not an RSV (respiratory syncytial virus). Institutions themselves have been a contagion of stupidity.

I wouldn’t say stupid. I think they were underprepared. Often there were contradictory messages coming out of institutions. Part of the reason is that they have been so badly funded for decades, because no one was expecting a pandemic of this nature. Aside from the fallout in mortality, which is enormous and cannot be underestimated, the economic fallout has been trillions of dollars. I wasn’t here but, of course, I certainly saw the photographs of migrants because of lockdowns. You are absolutely right… hand sanitisation is mostly a cosmetic feature. There continue to be institutional failings. They have been identified. I don’t think all of them have been corrected.

According to Mukherjee, there is a chance that if there is not another highly pathogenic strain of the virus, we may have an annual covid vaccine or perhaps one that covers most of the strains as they come along.
According to Mukherjee, there is a chance that if there is not another highly pathogenic strain of the virus, we may have an annual covid vaccine or perhaps one that covers most of the strains as they come along. (Getty)

How do you see the virus evolving?

I am not a covid expert, so I rely on synthesising knowledge from other people. What I know so far is there are two or three more strains beyond Omicron. We don’t know what’s happening in China. We don’t know whether there have been new variants. In an increasingly global world, it really becomes important for people to share this information, without which we are working in the dark.

You are a strong believer in ethics and your three books talk about ethics extensively. What is your take on the ethics of how nations, institutions and pharmaceutical industries responded to covid-19?

The idea that there were two worlds of covid is true. What happened in the US, in terms of both pharmaceutical and vaccine interventions, was very different to what happened in Asia and other places. As far as India is concerned, I think the Serum Institute (of India) did a valiant job of responding to covid. The pharmaceutical industry was initially very focused on the US. Ultimately a combination of embarrassment and pressure, and to some extent a real interest in stopping the pandemic, led them to realise that vaccines had to be made available to a much larger swathe of the population at a much lower price point. Ethically speaking, I think there was a gradual change, in the right direction of the response.

The realisation of the globality of the situation became more and more apparent, that the US and the Western world is not an island. Ethically speaking, now there is a sense that there will be more global surveillance and that the US, UK, Australia, New Zealand have to engage with the world. Otherwise, there will be another pandemic. And if the WHO doesn’t have enough funding, if international agencies don’t have enough funding, they will suffer the consequences.

In sequence of the books that you have written, what’s coming next?

Oh gosh. I am working on another book but I don’t know what it is.

Also read: Siddhartha Mukherjee: the magic and mystery of the cell

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