Saturday, 7 January 2017

* Gene genius Siddhartha Mukherjee on why ‘doctors shouldn’t be gods’

Jo Ellison
Siddhartha Mukherjee is a cancer geneticist, stem cell biologist, physician and assistant professor of medicine at Columbia University. A Rhodes scholar, who graduated from Stanford University, the University of Oxford and Harvard Medical School, he won the Pulitzer Prize in 2011 for his book, The Emperor of All Maladies: A Biography of Cancer. His recent follow-up, The Gene: An Intimate History, also received exceptional reviews.

All things considered, he makes for a rather daunting lunch companion. So I open our meeting with a devastatingly considered question: where do you get your jeans? Thankfully, the spry 45-year-old wearing a spriggy floral-print shirt, beard and rock-star quiff is not as intimidating as his CV might suggest. “A local tailor in India stitched them,” he says. “His name (really!) is Atul Jeans”.

We are eating at Dishoom, in London’s once derelict and now gentrified King’s Cross. It serves small plates of Indian classics in an atmosphere designed to recapture the spirited mood of the cafés founded by Zoroastrian immigrants in Mumbai in the 1960s. It has the strange, slightly discombobulating feel of a period-drama film set. Mukherjee, who left New Delhi at the age of 18 to study at Stanford University is already a fan. So I charge him with the order. “Are you vegetarian?” he asks. No. “Nor am I. How’s your spice tolerance? Medium?”

I tell him I can take the heat. “People make a mistake about Indian food, they confuse spicy with hot,” he corrects me. “Spicy means having spices.” So is it true I ask, that coriander tastes unpleasant to some people because they are genetically built to find it tastes like soapy water? “It depends on whether you’ve got the seed or the leaf,” he says as we each order a glass of champagne. “In New York, I only go to one store to buy leaf. I’m very particular about the leaf.”

Mukherjee is very particular about lots of things. He speaks in carefully modulated sentences, auto-correcting his meaning and adding qualifying clauses before committing anything to a full stop. He is also famously particular about his chosen specialisms. When he finished The Emperor of All Maladies, he thought he had nothing left “to tell.” But in the months that followed, he reviewed that opinion. If cancer was the end of everything then what about the beginning of it all? Or, as he writes in The Gene: “If cancer, to twist the description from Beowulf, ‘is the distorted version of our normal selves,’ then what generates the undistorted variants of our normal selves?” Hence The Gene became a story “of the search for normalcy, identity, variation, and heredity. It is a prequel to Emperor’s sequel.”

The Gene is a book of many stories. Its early chapters deal with the gene’s beginnings as a philosophical riddle, an abstract concept with no shape or form, as discussed by Pythagoras and Aristotle. It grew as a more fully realised concept through the work of Gregor Mendel, the 19th-century monk and autodidact who first identified “carriers of hereditary information” in his studies of pea shoots in Brno. It found physical form via James Watson and Francis Crick (and the lesser-credited Rosalind Franklin), who built the first model of DNA as a double-helix structure in their Cambridge labs in 1953. In the main, the history of the gene’s discovery was built on the obsession of a few extraordinary individuals, many of whom were very, very quiet, and some downright peculiar. Which of them would have made a good lunch date? “Franklin, definitely,” says Mukherjee of the stern, outspoken “brilliant” scientist who used X-ray photography to capture the structure of DNA and died cruelly young.

In the latter part of the book, Mukherjee turns to the bigger questions: how will the gene change our future; what can genetic testing tell us, and what will be the consequences? “Here is the question,” he explains as a plate of mini naan breads and raita is placed before us along with the lamb chops which, despite their heavy coriander seasoning, are quite delicious.

“If I said to you, there’s a whole family of things that you could screen for — potentially rare, but dangerous predispositions to diseases — would you want to know that information?”
Not really, I reply. What would be the point of living with the Sword of Damocles hanging over one’s head?

“Because, for our children, and increasingly for our generation, that option will be available. Potentially even before implantation, if you’re doing in vitro fertilisation. More importantly, it will be available for a price, and so we are looking at a society where one class can afford prenatal genetic testing, and another class cannot.”

My worry, I tell him, is that in editing out unpleasant features of our genome we will be, in effect, editing the society we live in. Saying no to things, and human lives, without any certainty of things becoming manifest. “Correct,” says Mukherjee. “Although of course, that’s the same logic as medicine. Medicine is trying to tell you what your future probabilities of illness are as well.”

Mukherjee has never mapped his own genome. “Because, for the illness I’m most interested in my family — schizophrenia — there are many genes. And we don’t know what they are. Or which ones confer higher risk versus lower risk. So I would get that information, and it would be for the most part unusable. It would be like reading a novel in which you only understand every fifth word. You could read the completely wrong novel.”

Right now in gene research even knowable things are hard to predict. “The [tumour-suppressing] genes BRCA1 and BRCA2, and some genes that increase the risk of having Alzheimer’s disease are knowable,” he tells me. “But even those are knowable in probabilities, and that’s a tiny fraction of what’s known. But, on the other hand, every year, as we learn to sequence the genomes of unborn foetuses, we will discover more and more about that. So things that I now consider are unknowable will become known and knowable.”

It’s tempting to think, as science continues to unlock the secrets of our existence, that DNA has become the new religion. “I think there’s certainly a trope in popular culture that DNA determines everything,” says Mukherjee, as he extracts a grilled prawn from its shell. “That, somehow or other, once we decipher genes, we’ll all of a sudden decode a human being. And it’s really worthwhile reminding ourselves that’s not true.” Why not? “We know [from twin studies] that even things that share a powerful genetic determinant are only manifest 50 per cent or 60 per cent of the time in the other twin. So there’s clearly something [else], whether it be chance, whether it be the environment. Or something that triggers a chain of reactions that change our genetic behaviour.”

Mukherjee has a terrific gift for making sense of seemingly impossible ideas. “Genes are set up in cascades,” he says. “One commands the other. They build a finger. They build a hand. They co-operate with each other. Although genes are known, and the code can be known, the process remains a little mysterious. It’s important to emphasise it’s a process.”

Do his studies or research give him cause for comfort or concern? “Both,” he replies. “I’m a cancer doctor. Every day, every week, we understand cancer in a new way, in a deeper way. The genetic technology has already transformed the way we treat cancer.”

The outcomes of cancer are improving, too, although Mukherjee prefers to talk about “decreased mortality rates” rather than “survival rates”, because “if you diagnose cancer earlier, you can falsely believe that people are surviving longer. And that’s a fallacy. But based on studies on the US, we’ve begun to see a significant decline in [age-adjusted mortality rates] of about 1 per cent or 2 per cent every year.”

Those are the positives. What about the negatives? “Is it worth it in terms of the cost for the quality of life?” he replies. “You can ask deeper and deeper questions. But we need to have the vocabulary to ask the right kind of questions.”

We take a pause, during which I realise I have eaten a bigger share of the sharing plates than Mukherjee, who has only eaten a few prawns and a bit of lamb. The rice is untouched. I polish off a black bean dal and consider it might have been hotter — and spicier.

Gene research is astonishing: wonderful in its ambition, and humbling in its reach. But it doesn’t get around the fact that we’re still going to die. I wonder if unlocking the genome has made us any more able to face our own mortality, — or just served to chase it further away.

“I think we still need to rethink some fundamental things about dying,” says Mukherjee, who, like physician and fellow New Yorker writer Atul Gawande, daily treats people facing end-of-life care. “And one of the things which I know, as a doctor, is that even when you’ve made a global peace with the idea of mortality, the process of getting from being sick to dying is still very turbulent.”

“It’s not death that worries us,” he continues. “It’s dying. The questions people ask — will there be pain? What will I feel like? They’re not asking what will it be like to be dead. They’re asking you what is the process like? We’re culturally bereft in that sphere still. And I think we have become even more so. Our rituals of dying have decreased. And when you remove some of the traditional rituals around dying we need to replace them with other things . . . that allow a good death.”

As a physician in an increasingly secular society, Mukherjee is often elevated to a role akin to a confessor or priest by his patients. “There’s obviously some power there,” he shrugs. “Even today, there’s a shamanistic quality about medicine. And if you’re a doctor, you will be imbued [with that], whether you like it or not. So it’s important to try to defuse that. I don’t think that doctors should be gods. It ultimately becomes an intrusion. It erects a set of boundaries and walls.”

Does Mukherjee believe in God? “Mostly no,” he says. “I’m mostly agnostic. I can imagine powers that are beyond comprehension, and therefore necessitate a spiritual moment with that idea. But I don’t believe in a person who lives in another space who has dicta to give us.” Neither does he believe in life after death.

The waiter comes to take away our plates and offers us a dessert. We agree to share a chilli ice cream, which Mukherjee is curious to try and which turns out to be quite fiery. Now, he’s dealt with cancer and the genome, he is thinking about his next field of inquiry. He has a deep fear in life of being “creatively stuck” and feels a “compulsive” need to ask questions. Moreover, he sees writing as a way of taking a “side exit” from the highly competitive world of purely scientific research.

“I’ve become very interested in the future of medicine. And what it will look like 10, 20, 100 years from now. What if we could take the untapped universe of molecules in our brains and bodies and start imagining them as the targets of drugs? We’re working in medicine in a tiny corner of the universe... What if that began to widen?”

In the future, Mukherjee says, medicine will be more targeted, while stem cell technologies will allow us to “re-engineer immune systems”. He’s growing cartilage in his lab. “Because cartilage, as you know, is one of the organs that degenerates and never comes back. Half the world is bent over, not because of their bones, but because their cartilage is gone. There was a controversial report out recently that says we might live until we are 115 years old. But not all parts of our body will survive until we’re 115. In future, we’ll be able to re-engineer parts of the body.”

Which sounds great but, as my grandmother would say: who the hell wants to live till 115 anyway?
Mukherjee is carrying with him a very small suitcase; “a 10-day bag”, as he describes it. Later this afternoon he will fly to India, before returning to his wife, the sculptor Sarah Sze, and their two daughters in New York. Before that, however, he will go to Google’s London offices to discuss the use of artificial intelligence in the future of medicine. Will robots one day be our doctors? Mukherjee is not against using them as a diagnostic agent, but is cautious of a medical system in which we have lost a “humanistic quality. Physicians don’t even touch their patients these days,” he says. “And there’s something terribly lost . . . When someone comes in and they’re desperately sick, you should be able to tell. You don’t need a test.”

As we finish the ice cream, I wonder that Mukherjee’s genetic gifts may have been somewhat overgenerous. The Rhodes scholarship, stunning scientific record and insatiable curiosity are fine. But then to go and win a Pulitzer Prize for writing seems a little greedy. Is he unbearably driven?
“Actually, I’m not a very competitive person,” he says. “People find it unfathomable, and you’d have to ask my wife, but it doesn’t come naturally to me. I think it’s helpful to have goals and then be immensely flexible about them,” he concedes. “But yes, my genetic flaws are many. I have so many flaws I can hardly count on my fingers. I get very easily disappointed with projects, and then I start suffering through them. I have a very binary relationship with tenacity. I’m hopeless at anything that requires hand-eye co-ordination of any sort. Ping-pong: I smash the bat in my face. I’m terrible at handiwork. I can’t fix things. Oh, and here’s a good one, I have absolutely no sense of direction.”

Now an American citizen, Mukherjee despairs of the politics of the president-elect, Donald Trump, and “his steadfast failure, or refusal, to believe in science. He’s said things about climate change that make no sense.” Populist ideas have proven very dangerous in the history of the gene, where the spectre of eugenics still casts a dark shadow, and Mukherjee worries about his research being misused for political means. “The Gene has a huge and very contentious chapter on race,” he says. “There’s a deep trend emerging [in politics] about racial determinism. And no matter what you say, no matter what you write, the racial determinists will contort your writing to make it seem as if you’re saying what they want you to say. It’s astonishing.”

Mukherjee’s meeting awaits. He signs a copy of The Gene and he’s off, wheeling his bag urgently towards the Google complex. So far as I can tell, he’s heading in the right direction.

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