Siddhartha Mukherjee | Unraveling the Human Genome

The Gene: An Intimate History begins with the intimate history of the author's own family. Haunted by the recurring presence of schizophrenia, Mukherjee describes in heartbreaking detail the inherited horror that has burnt its way through the generations of his family tree.

This preoccupation with his own genetic makeup was the catalyst for this book. The Gene is a fascinating glimpse into the world of genetics, from its early conception in the gardens of Gregor Mendel’s Monastery, to its ugly re-appropriation by eugenics movements in the early 20th Century.

But crucially, The Gene also looks to the future. Mukherjee has said that the book was written with a sense of urgency, as scientists begin to find ways of manipulating the human genome. Gene editing is a subject riddled with ethical concerns and Mukherjee believes it is an issue that needs to be understood and debated by everyone, as soon as possible. 

I expected to find quite a straightforward academic history of genetics in this book, and instead found a very personal story. You could have written this book and not included your personal history. What made you decide to put your family in there?

I actually don’t think I could have written the book without including that story. That story, or the series of stories really, is what motivated me to write the book. This book is a necessarily personal book and I wanted to make that clear for myself as well as for my readers upfront. Genes are not the things that one thinks of in the laboratory, far away from ourselves. They are something that affects my life and your life. Our understanding of genetics must have personal and cultural resonances, and that’s the reason I started working on this book.

Obviously there were personal parts that were very hard to write. In comparison to my last book it was much harder to write and research. I learnt more. And this one is very personal, so that element looms large in the book.

The science in the book is also very accessible. Why do you feel that it's important for the public to understand what's happening with genetics at the moment?

I think it’s important for people to understand the power of genes as well as what the constraints are. We need to have a very frank discussion about what happens next. We’re on the verge of trying to decipher what the genome tells us about our individual cells, about our propensities for illness, about the way we think about the future. So we need to understand the vocabulary, and what the background and the context is. We need to understand the history of eugenics to understand what will happen as we begin to tamper with the human genome and change the way we think about ourselves. All of these issues are relevant to contemporary culture and so the book has to be written in a way that we can understand without getting lost in the depths of the technical details.

It seems a lot of the time that when this issue of gene editing is being discussed that the scientists are in favour and the public is more wary. Sometimes it can be hard to distinguish reality from media-fuelled fear. For example you have talked about the possibility of synthesizing the entire human genome and creating it from scratch. How far away are we from this reality?

That’s a discussion even I heard of after the book had been launched, so that’s just a reminder of how relevant it is. In the public realm there’s a big buzz right now around whether we can artificially synthesize the human genome. I don’t know how technically possible it is to do right now, but at least the question has been asked. Once you ask the question you are stepping into areas of the unknown.

I don’t think it’s fair to say that scientists are in favour and the public is wary. Scientists are wary too. There’s a massive informed discussion going around right now throughout the world about the extent to which the human genome should become territory to manipulate. There are plenty of scientists who are wary and members of the public who are pro. The pro and against is not the real concern here. The real concern is that we learn the vocabulary so that we can have an honest discussion about what happens next.

Another exciting possibility you have talked about is the ability to cut a piece of the human genome out, for example the gene that causes Alzheimer's. 

There is no simple gene for Alzheimer’s. Very few diseases that we know have gene variants that will autonomously reciprocate the disease. That’s a rarity. It’s vastly more common that gene variants have influences and they work in constant with each other and with the environment. So the first thing to say is that I don’t think we’d be able to take out the gene for any disease in the near future. But there are technologies that are becoming available that allow us to manipulate the human genome in ways we couldn’t before.

You also mention the possibility of doing the exact opposite, of adding information to the human genome. Does this mean you could theoretically apply a specific trait to an embryo?

The technologies that allow us to make specific cuts in specific parts of the human genome are becoming more and more available every day. I’m using these techniques in my own work in my own lab. To what extent these technologies are specific and how safe and how easy they are, is a question that’s really raging through the scientific community right now and we’ll never know all the answers, but we’ll soon know the answers to many of these questions.

Let's talk about your area of work, oncology. How have recent discoveries in genetics impacted the field of cancer treatment?

Well there are two kinds of discoveries. One is sequencing the genome and understanding what kind of genes are altered in cancer cells. That’s had a huge impact on my work trying to understand what these gene variants and mutations do. And second, we are using CRISPR and Cas9 technologies to change genes in stem cells and other cells, to try to understand how these genetic changes might precipitate malignant behaviour. We’re doing that more and more and the technique is surprisingly successful. Of course in our hands it’s all done in the laboratory setting. We’re not trying to alter human genomes in embryonic stem cells. That’s not our work. But one thing that’s very clear is the astonishing dexterity with which we can use these technologies.

One of the most fascinating elements of the book is the history of genetics and how various scientists, arguably beginning with Mendel, began to piece together this mystery. Which of these figures was the most interesting to you? 

I was particularly fascinated by Mendel’s work because I didn’t know it very well. I had to read up on it and I actually went to visit Mendel’s monastery. It was really enlightening to go and look at the place where he worked. I didn’t even know that Mendel didn’t coin the word gene. The word gene came more than forty years after his work. He was almost completely overlooked in his own time and was rediscovered much later. The gardens where he did his famous pea plant experiments have changed somewhat but they’re still there, so it was wonderfully interesting.

Would you agree that the book acts as a kind of warning? The way it's structured really highlights how this exciting new discovery and the desire to understand and to do goof resulted in the evil we now know as eugenics. 

There are parts of the book that warn us about the future, and parts of the book that tells us about what the past has been. It has a massive spread in terms of time. It starts in ancient history and moves forward, so there’s a lot of territory that’s covered. Some of it is a warning. Some of it is a careful consideration of the future based on what we know from the past.

But I don’t think we will see state mandated eugenics with gene editing in the US or the UK. I just don’t see that happening. What I do see happening is a kind of personalised form of eugenics in which you can potentially sequence the genes of your unborn child and make decisions about that child. That technology is already available to us, the sequencing technology, but the interpretation is not. In a sense I wrote the book to pre-empt what might happen as we start to interpret that information. You know, what if we found a gene variant that increased the risk of a disease by 20 percent?

It would make sense to remove that gene variant right? 

I don’t know what would make sense. I really don’t. What would make sense is to have a large discussion about what happens as we move forward and to at least understand the vocabulary and the constraints. It’s very important to know that for most characteristics or traits it is not on gene but multiple genes and most of them are influenced by the environment and by gene-gene interaction. So we have a situation where we need to understand what that landscape looks like before making claims.

But even if we decide in Britain or the US to put rules on what can and cannot be done with these technologies, some other nation, China being the most obvious candidate, may well go ahead with things we've labelled as ethical no-go areas. 

Yeah, the exact area of international law that governs moratoria on human embryonic manipulation is unknown to me. But there’s a sense that different cultures will have different ways of thinking about it. As you know, in China there was already an attempt to try and manipulate non-viable embryos. How that plays out in the future is something we have to think carefully about. There’s already been a call for an international moratorium on making genetic changes in human embryos. I think that’s wise.

Do you think it's possible to have an international consensus on something like this?

With recombinant DNA there was a track record of scientists agreeing across countries to not do certain experiments and that really started because of a meeting that allowed these constraints to be put in place. I think we need more and more meetings of that sort. There are laboratories all over the world in India, China, Korea and other places that already have technologies to manipulate the human genome. So we need to create a consensus about what is possible and what is not possible. What’s safe and what is not safe. Actually, right now an equally large concern is manipulating genomes and making things that are released into the biosphere.

"What I do see happening is a kind of personalised form of eugenics in which you can potentially sequence the genes of your unborn child and make decisions about that child."

SIDDHARTHA MUKHERJEE ON THE FUTURE OF GENE SPLICING

How much of our personality is really determined by genes? 

The quick answer is that genes and environment interact to produce unique variants and that answer is not going to be modified for a while because it really seems to ring true across scientific studies. It’s not going to be all nature or all nurture for many traits, some are going to be dominated by nature. Many of our anatomical forms are dominated by nature, that’s why you and I look like each other. But environment plays a big role in the way those anatomical forms eventually manifest. To give you an example, if you have an accident obviously your anatomy changes and that has nothing to do with the genes you were given.

You have also said, "we've made an armistice between genes and environment, and this is a fools armistice."

Yes, for precisely that reason I gave. It depends on what question you’re asking. If you’re asking the question – is the fact that we have five fingers in our hands a product of nature plus nurture? No, absolutely not. There are strong anatomical constraints. So really whether genes or environment dominates depends on the question you’re asking, and confusing that idea creates a false armistice.

I don’t agree that biology is destiny. I think some aspects of biology have a strong influence on destiny. Other aspects have less influence on destiny. Making such blanket statements really should provoke the question, what aspect of destiny are we talking about? To what extent are we talking? Is it a real number? Is it a percentage? And so forth.

"I don’t agree that biology is destiny."

Could you explain previvorship? It's a fascinating concept and something I hadn't heard of before. 

I think it’s an Orwellian word. A previvor is someone who is a survivor of a disease that they haven’t had yet. By that I mean that we’re predicting futures from our genetic code, and often you may not have the disease that’s predicted. A classic example is breast cancer. Women can be identified as having a mutation in the BRCA1 or BRCA2 gene, but they may not have breast cancer. Not all women with that mutation will have breast cancer in their lifetime. So the question that’s raised is, what happens to you as an individual when you know that you have a risk for the disease but you haven’t had the disease yet? That’s a question that’s becoming more and more urgent in our culture. The ethics surrounding that are complex. Obviously it creates labelling, it creates stigma, it creates anxiety. Is that anxiety worth it? Well it depends what we’re trying to diagnose and it depends what the penetrance is of the disease.

You write at length and very movingly about your father's side of your family. Has your father read the book?

My father is not well but he’s read parts of the book. My family is proud of it because it’s a personal book, though it raises very deep questions within all of us.

What do you want people to take away from the book?

I want to give people the vocabulary and the thought process that allows them to think about these issues carefully in the future. I think we need all of that to move forward before we make major decisions about what to do in terms of reading and writing genomes.

This article was originally published in 52 Insights Magazine