Cancer, mutations and the facts of life

Cancer, mutations and the facts of life

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Bob Weinberg of the Massachusetts Institute of Technology has been one of the world’s foremost experts on cancer for nearly five decades. Back when I was a wee graduate student, I lunched with Dr Weinberg at a conference and he told me something that stuck with me: “If you live long enough, you will get cancer.”

The inevitability of cancer has made itself painfully clear over the past century. As mortality from almost all other causes has plummeted, cancer rates have skyrocketed. While there is good reason to believe that some aspects of modern lifestyle and diet also contribute, the bulk of the rise in cancer is simply because we are no longer dying from so many other things.

In the early 1900s, the leading causes of death were, in order, pneumonia, influenza, tuberculosis, and gastrointestinal infections, mostly cholera. Thanks to vaccines and other public health measures, these have largely been conquered in the developed world. Even deaths in accidents have been cut by half, per capita, over the past 100 years. We live longer and healthier lives than ever before.

Until we get cancer.

But why is cancer the beast that stalks us all? What is it about this disease that makes it inevitable? And why is it the price we must pay for many incredible evolutionary advances? To understand this issue, we need to go way back in our evolutionary history. Way back. I’m not talking about “early humans” or ancestral primates, or even the origin of vertebrates. The story of cancer begins all the way back when a single-celled organism began to stick its cells together and started down the evolutionary path towards multicellular animals. That happened around 800m years ago.

The story begins that long ago because that’s when our ancestors had to deal with a new, extremely complicated challenge – that of organising many cells into one organism – which was not something that their single-celled precursors had to contend with. In a single-celled organism, every cell is a life form unto itself. Every time a cell divides into two, those two cells go their own way as independent creatures. In multicellular organisms such as plants and animals, there has to be a way to organise and coordinate cells. Each cell must “know its place”, so to speak, which means to take the proper shape and do whatever it is supposed to do, whenever it is supposed to do it.

Even more important, there needs to be a way to control and contain cell division. Each cell must divide when it should, and not divide when inappropriate. A few cell types constantly divide, some rarely or never, and most can divide but do so only when necessary. When cancer strikes, it is because these control mechanisms have gone wrong. Tumorigenesis begins when a single cell forgets its place and starts multiplying out of control. As Sir Paul Nurse, who was awarded a Nobel prize for his discovery of one of these control mechanisms, frequently says, “cancer is a disease of cell division”.

The reason this uncontrolled division eventually causes a life-threatening condition is because as cells continue down this path, they become deprogrammed and morph into shapeless and mindless zombies, forgetting how to do anything but reproduce. They then take over the organ in which they live, spread to other organs and take them over too, crowding out healthy tissue as the zombified cancer cells outgrow the non-cancer ones. This process of de-differentiation is progressive, which explains why treating cancer gets more difficult as the disease continues, eventually reaching the point where we simply cannot stop it. As American essayist Edward Abbey put it: “Growth for the sake of growth is the ideology of the cancer cell.” While he meant this as a critique of capitalism, he nailed the essence of cancer as well as any scientist has.

What causes cells to lose their programming in the first place? The answer is mutations, but of a very specific kind. As early animals began to organise their cells into different tissues and eventually organs and complex bodies, they evolved a series of switches in order to control cell division. We can oversimplify by putting these switches into two broad categories: pro-growth and anti-growth. The pro-growth switches are those that help coax cells into dividing and multiplying, while the anti-growth switches shut the process down, restraining proliferation so that cells only multiply when called upon to do so. All cells have these accelerator pedals and brake pedals to help tissues function properly.

Then come the mutations. Mutations are random changes to our DNA, the genetic material that contains all the encoded information our cells need to function. These random changes are always happening, in part because of exogenous things such as chemicals and radiation, but endogenous molecules, normal by-products of cell metabolism, can also cause mutations.

By far the most common way that we get mutations is through DNA copying errors. Every time a cell divides, it must copy the entire genome so that both daughter cells have the full set of DNA instructions. The human instruction manual is very long, though. Each chromosome has millions of DNA letters for a total of around 6bn nucleotides, the letters of the DNA language. When we copy this staggering number of letters, mistakes are inevitable. Even with the incredible fidelity of our DNA replication apparatus and the many overlapping proofreading and repair factors, a few mistakes do get through each and every cycle.

pioneering cancer researcher robert weinberg in his lab



Pioneering researcher Dr Robert Weinberg: ‘If you live long enough, you will get cancer.’ Photograph: Gail Oskin/AP

Every cell in your body is the result of at least several thousand rounds of cell division, some into the millions. This means that every cell has thousands of mutations that make it a little bit different from the single-cell zygote you started as. These mutations happen randomly, like lightning strikes occurring around the genome. Because so little of our genome is strictly dependent on precise sequences, most of the lightning strikes are harmless. Occasionally, though, lightning strikes a gene.

If a mutation happens in one of the genes that are part of the “anti-growth” switches that keep cells from dividing when they’re not supposed to, that cell and its descendants are a potential problem. Probably not right away, but since these cells are lacking part of their self-protection against becoming cancerous, they’re a lurking danger. It’s like you’re driving and your brake line gets cut. You won’t notice anything until you need to brake. Then you’re in trouble. We call these anti-growth genes tumour suppressors because that’s exactly what they do. A single tumour suppressor called p53 is mutated in 50% of all cancers.

The loss of a tumour suppressor is just the first step and it isn’t enough to cause cancer. Those cells usually grow and divide a little too energetically, but nothing our bodies can’t handle. If, however, another mutation occurs in one of these cells that has had its brake lines cut, that’s when the real trouble can begin. Very rarely, the random bolts of lightning strike within a pro-growth gene and, instead of deactivating it, the mutation hyperactivates it. These pro-growth genes are called proto-oncogenes because, when properly mutated, they become oncogenes and drive a cell to proliferate out of control and begin the process of becoming despecialised, mindless zombies. Nearly a quarter of all cancers are caused by a proto-oncogene called Ras, co-discovered by Bob Weinberg, but there are hundreds of these little powder kegs, just waiting for a spark.

The morbid reality is that every time a cell in our body duplicates its DNA, we’re rolling the dice. Thousands of mutations are happening in your body right now as you sit reading this article. It’s only a matter of time before one of them hits a tumour suppressor and, some years later, another hits a proto-oncogene. This is a simplified view, of course. The reality is that you need to rack up another couple of mutations before a cell and its descendants become truly dangerous. The life history of a particular tumour spans many years, even decades, from the first mutation until it reaches its final, lethal form.

This is why catching cancer early is so important. Since around 1990, some two decades after Richard Nixon first declared the “war on cancer” in the US, we have finally begun to make progress on reducing the mortality of cancer. Some of that progress has come from a few technological innovations such as rational drug design, but most has come through enhanced modes of early detection. Catching cancer before it becomes a malignancy spread throughout the body is the only hope for a cure. Aggressive combinations of surgery, radiation, and chemotherapy can often completely eliminate cancerous cells that haven’t yet accumulated too many mutations. In these cases, patients can enjoy a full recovery – until they get cancer again. By the time we’re in our 40s, we are likely to have hundreds of premalignant cell populations, but the vast majority will either be destroyed or held dormant by our own anti-cancer defences. With each passing day, however, more rounds of cell division mean more DNA copying and more chances for further mutation. It’s a game of dice. With good genes and a healthy lifestyle, we can beat the odds for a while, but the house always wins eventually. One of those random lightning strikes will push a cell over the edge and send it into overdrive. Bob Weinberg was right. If you live long enough, you will get cancer.

Mutations, then, must be our most vicious enemy, the ultimate undoing of our happy lives. Seen from our point of view, it certainly seems that way. But we must never forget that mutations are the source of all diversity and all evolutionary innovation. From the very first emergence of a proto-cell from the primordial soup, with its budding genetic system of DNA or, more likely, RNA, all advances in complexity and innovation have come through mutations. If DNA replication were perfectly accurate, we’d never have progressed past the point at which life first evolved. As Dr Lewis Thomas, one of the first physician-scientists to write popular essays, put it: “The capacity to blunder slightly is the real marvel of DNA. Without this special attribute, we would still be anaerobic bacteria and there would be no music.”

We will fight the effects of mutations our whole lives, a fight that we will ultimately lose. But on larger scales of time, mutations are essential for our species and for our future. Every single step in our evolutionary path, from the development of a backbone, to our upright posture, and the growth of our massive brains, has occurred through the same random mutations that will ultimately kill us. It’s a bittersweet irony. Mutations: can’t live with them, can’t progress without them.

Human Errors: A Panorama of Our Glitches, From Pointless Bones to Broken Genes by Nathan H Lents is published on 3 May 2018 (W&N £16.99). To order a copy for £14.44 to to guardianbookshop.com or call 0330 333 6846. Free UK p&p over £10, online orders only. Phone orders min p&p of £1.99



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