Fifty years ago, US President Richard Nixon declared a “war on cancer” when he signed the National Cancer Act. Despite fantastic progress on some fronts, overall it is clear that we are not winning this battle. Cancer remains one of the leading causes of human mortality. But what if the tired war-metaphor is getting it all wrong? Brimming with thought-provoking questions, The Cheating Cell looks at cancer through an evolutionary lens and forces the reader to radically reconsider cancer; not as a bug, but as a feature of life.
The Cheating Cell: How Evolution Helps Us Understand and Treat Cancer, written by Athena Aktipis, published by Princeton University Press in March 2020 (hardback, 238 pages)
Athena Aktipis came to the research field of cancer evolution in the mid-2000s, just as it was getting a boost from various researchers, including Mel Greaves, who started to apply ideas from evolutionary biology to cancer research. She describes herself as working at the interface of cooperation theory, theoretical evolutionary biology, and cancer biology. Her background in psychology, with a specific interest in cooperation and conflict, might seem little relevant to cancer research but turns out to be highly appropriate.
The basic premise of this book is that cancer is an evolutionary phenomenon that has been with us for as long as life has been multicellular and is best thought of as cellular cheating. If that seems like a lot to take in, I am trying to distil into one sentence what Aktipis spends the first three chapters developing. Let us go through these in reverse order.
First, this notion of cheating. The hallmarks of cancer in humans is unchecked cell division, frequently forming tumours in the most unwelcome of places and, in some forms, spreading throughout the body in a process known as metastasis. But this is rather a narrow definition for understanding cancer’s deep evolutionary history. To compare organisms with a very different underlying biology, such as plants and animals, you need to think at a more fundamental level. What cancer cells are ultimately doing is cheating on the pact that cells form when cooperating to form a multicellular organism. They divide out of control, they refuse to self-destruct via programmed cell death (apoptosis), they hog the body’s resources, they do not stick to their assigned job, and they trash their environment, damaging and destroying the host’s body as they go.
“What cancer cells are ultimately doing is cheating on the pact that cells form when cooperating to form a multicellular organism.”
Second, this notion of its deep history. The option for some cells to go rogue and cheat became available as soon as life evolved multicellularity. As also further explored in chapter 5, some form of cancer is found in almost every animal group and even in plants, where it is known as fasciation. This chapter also explores Peto’s Paradox: how larger body size is associated with increased cancer risk within, but not between species. Large and long-lived species consisting of many cells, such as elephants and whales, are very resistant to cancer.
Third, this notion of an evolutionary phenomenon. Individual cancer cells reproduce rapidly and, just like organisms, are subject to natural selection. Populations of cancer cells show variation, heritability, and differential fitness—this is how they thwart our medical interventions, developing resistance to drugs and chemotherapy. Even if the time-scale is short and cancer ultimately kills its host, until then the calculus of evolution through natural selection still applies. Furthermore, selection is happening simultaneously at multiple levels. There is an arms race between rapidly evolving cancer cells and the body that, through division of labour, can draw on more complex defence strategies. Aktipis introduces you to three mechanisms that offer a certain redundancy in keeping cells from misbehaving. There is the intrinsic mechanism formed by the cancer suppressor gene TP53 that acts as a central node, incorporating information from many sources to decide whether to initiate DNA repair, apoptosis, or block cell replication. There is a neighbourhood mechanism, with cells requiring so-called survival signals from their neighbours so as not to initiate apoptosis. And there is the systemic mechanism of our body’s immune system detecting and destroying inappropriately behaving cells. Cancer can break or hijack all of these mechanisms.
Probably the biggest eye-opener for me was what I mentioned first: cancer being a feature, not a bug. In chapter 4, Aktipis outlines how cancer is with us from “womb to tomb”. The reason evolution has not overcome cancer is trade-offs. The very processes that, when they malfunction, cause cancer are the basic mechanisms that, when they function, allow us to exist as multicellular organisms in the first place. “Many important systems that help us survive and thrive require cells to do things that are “cancer-like” including proliferating rapidly, moving around the body, and invading tissues” (p. 55). Think of wound healing and tissue regeneration, for example. Aktipis introduces the metaphor of life walking a tightrope: there needs to be enough cellular freedom to allow an organism to grow and develop, but not so much that cell division runs rampant. This, here, is why the war metaphor is unhelpful: “We can’t completely eradicate something that is fundamentally a part of us” (p. 10).
“The very processes that, when they malfunction, cause cancer are the basic mechanisms that, when they function, allow us to exist as multicellular organisms in the first place. […] This, here, is why the war metaphor is unhelpful […]”
Aktipis has many more arrows to her bow. A long sixth chapter probes the frontiers of cancer research by asking what lesson from ecology we can apply to the tumour’s microenvironment. Can dispersal theory be applied to metastasis? Is the cooperation seen amongst cancer cells an adaptation, a by-product of other processes, or a transitory, random process? Can we draw lessons from kin selection theory or social insect colonies? What of the interaction between cancer and the microbiome? And can selfish genetic elements such as transposons influence our susceptibility to cancer? There is a huge blind spot here, claims Aktipis, in that current genomic sequencing technologies cannot detect extrachromosomal DNA, so it is hard to make links to cancer. The consequences could be dramatic: “the theoretical foundations of much of the field of cancer evolution would have to be reconsidered if cancer is, in part, a result of selection at the gene level favoring selfish genetic elements […]” (p. 158).
All of the above should force us to rethink how we treat cancer, leading to seemingly counterintuitive treatments. Our current strategies of radiation and chemotherapy rain down fire and brimstone but often lead to drug resistance. Rather than total eradication, adaptive therapies would aim for coexistence with tumours at a level that is not too damaging for the patient. For other cancers, feeding tumours and providing a comfy, stable environment could prevent the more disruptive result of metastasis. These are but some of the options and ideas considered here.
Aktipis is very interested in science communication and has enlisted Alex Cagan to provide infographics. I found her writing a tad repetitive in places, saying something in one paragraph and then repeating it in slightly different words in the next paragraph. Hopefully, the flipside of this particular quirk is that few people will be left feeling they did not understand concepts. And this is, in a way, a good thing: The Cheating Cell bristles with fascinating ideas, there are many other tangents and questions Aktipis raises that I have not mentioned.
“All of the above should force us to rethink how we treat cancer, leading to seemingly counterintuitive treatments.”
One final question to consider (I swear books are like buses sometimes; you wait for ages and then two come along in quick succession): how does this book compare to Rebel Cell? Published in 2020, science writer Kat Arney explores the same topic. Though I have not read it, a critical reviewer on Amazon UK felt it does not reference its sources properly. This is where The Cheating Cell shines, backing up statements with published research in a 30-page notes section.
The Cheating Cell makes for fascinating reading and forces a radical reconsideration of what cancer is and how we should deal with it. I will leave you with what I consider Aktipis’s most powerful and sobering call to action: “We have much to gain from accepting that cancer is a part of us and preparing for a long-term strategic interaction with it as an unpredictable and adaptive counterpart. It takes courage to face this truth and accept an uncertain future with cancer rather than hanging onto false hope that we will one day find a magical weapon that can target and eliminate cancer from the world.” (p. 182).
Disclosure: The publisher provided a review copy of this book. The opinion expressed here is my own, however.
Other recommended books mentioned in this review:
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Following my two earlier reviews of Convergent Evolution and Convergent Evolution on Earth, this is the final of three reviews of MIT Press books in The Vienna Series in Theoretical Biology dealing with convergent evolution, something I consider to be one of evolutionary biology’s most exciting topics. Are evolutionary changes happy accidents, i.e. contingencies? Or is there a law-like repeatability underneath, explaining why some traits evolve time and again, i.e. convergence? Is it even a matter of either-or? And what lessons does this hold for life elsewhere in the universe? Philosopher Russell Powell wrestles with these questions in a manner that is as rigorous as it is intellectually rewarding. Evolutionary biologists will want to give this excellent book a very close read.
Contingency and Convergence: Toward a Cosmic Biology of Body and Mind, written by Russell Powell, published by MIT Press in February 2020 (hardback, 308 pages)
Powell starts by examining the legacy of Stephen Jay Gould, the famous evolutionary biologist and science populariser who tragically passed away in 2002. In his book Wonderful Life, Gould proposed the thought experiment of rewinding the tape of life to see how it would evolve on repeat plays. Based on the exceptional Cambrian fossils found in the Burgess Shale in British Columbia, he argued that lifeforms would be radically different, contingent on small variations that amplified with time. Others criticised this idea by pointing to the many examples of convergent evolution, the ubiquitous pattern of evolution repeatedly hitting on the same or similar solutions to a problem in different organisms.
Before proceeding, however, Powell offers a surprising little detour into astrobiology. Since we cannot rewind the tape of life, the next best thing would be to see how life evolved elsewhere. Just some of the interesting topics considered are the anomaly of life’s single origin, the timing of the emergence of intelligent, multicellular life compared to the lifespan of our Sun, and the problem of the observer selection effect. Where I found the previously reviewed Convergent Evolution on Earth lacking in its lessons for astrobiology, Powell engages with this topic in a far more thorough manner. Despite decades of effort, the stars remain eerily silent. Which brings us back to contingency and convergence as the third best option to answer Gould’s questions.
But what, exactly, did Gould have in mind with evolutionary contingency? And does the criticism from convergence really engage with his argument? These are the kinds of deeper questions that Powell explores in the first half of his book.
“Some, […] have interpreted contingency as meaning non-repeatability, others […] have equated it with unpredictability. Neither is correct, writes Powell.”
See, the problem is that Gould never clearly defined contingency, nor used it consistently. His idea remains, as philosophers put it, underspecified. Like others before him, part of Powell’s mission here is to piece together what Gould intended, based on a close reading of especially Wonderful Life and the magisterial The Structure of Evolutionary Theory. Laying bare the theoretical underpinnings of, as he dubs it, Gould’s “radical contingency thesis” is an incredibly instructive exercise. Also because it explains how Gould has been misinterpreted and why the critique from convergence often descends into “dismantling “straw man” versions of Gould’s thesis” (p. 101).
Some, prominently Simon Conway Morris and George McGhee, have interpreted contingency as meaning non-repeatability, others (myself included) have equated it with unpredictability. Neither is correct, writes Powell. Gould’s argument of contingency applied specifically to conditions in the early Cambrian: “small changes [here] would have led to a very different initial occupation of morphospace” (p. 43). But he acknowledged that, after this, many body plans became “developmentally entrenched”, something that has been confirmed by research in the field of evolutionary developmental biology, or evo-devo. Evolution prefers the easier option of reusing and repurposing existing structures. So, with time, the layers upon layers of interacting genes and regulatory networks laying out gross body morphology became too hot to touch for evolution, with mutations often being lethal.
Powell here makes a distinction between deep and shallow replays of the tape of life. The problem is that most examples of convergent evolution that are being wielded as overturning Gould’s contingency are of the shallow kind. Seen this way they are not that surprising, a point Jonathan Losos also raised in Improbable Destinies. According to Gould, convergent evolution cannot overcome developmentally entrenched body plans, their existence remains a matter of contingency—or so argues Powell. This points the way to the kinds of evidence required for a more convincing critique of contingency.
“Powell here makes a distinction between deep and shallow replays of the tape of life. […] most examples of convergent evolution […] are of the shallow kind.”
In my opinion, the first half of this book is obligatory reading for evolutionary biologists. The text will require your close attention, but it is engagingly written and incredibly rewarding. Do not be intimidated by the table of contents, but do expect to have to look up some words: I doubt that many outside of philosophy circles regularly speak of exegetical shortcomings or the “nomological vacuum of biology”.
The second part, which is more Powell’s personal challenge to Gouldian contingency, argues that, next to bodies, minds and cognition are highly convergent evolutionary outcomes. Partially for the sake of brevity, and partially because the first half is such a bombshell, I will be glossing over this second half. It is no less interesting, though it is the tougher part of the book, dealing as it does with slippery concepts such as cognition and consciousness.
Briefly, the starting point is the evolution of “image-forming sensory modalities”; a broad definition of vision that includes echo- and electrolocation. The ability of organisms to access real-time, detailed representations of their environment has been hailed by some as the kick-start for evolution, heralding the Cambrian explosion. It also led to the evolution of—borrowing and adapting the German term Umwelt from 19th-century biologist Jakob von Uexküll—Umweltian cognition and consciousness. Without going into the many subtleties Powell discusses here, this can be very coarsely defined as your “first-person portal on the world” (p. 212). This also entails fascinating discussions of the evolutionary history of brains and neurons, and behavioural evidence of sophisticated perception and cognition in invertebrates, specifically in cephalopods and insects.
Overall, I was very impressed with the depth and rigour of Contingency and Convergence. It provides the intellectual challenge and reward you would associate with this book series. Powell not only provides a valuable analysis of this debate but also challenges readers to engage better, both theoretically and empirically, with contingency and convergence in evolution. Without a doubt, this is a must-read for evolutionary biologists.
For those interested in second and third opinions, I recommend you also check out reviews by fellow bloggers bormgans and Jeroen Admiraal.
Disclosure: The publisher provided a review copy of this book. The opinion expressed here is my own, however.
Other recommended books mentioned in this review:
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“Life Finds a Way: What Evolution Teaches Us About Creativity“, written by Andreas Wagner, published in Europe by Oneworld Publications in June 2019 (hardback, 304 pages)
Wagner begins by introducing the central concept of this book: the adaptive landscape, a powerful metaphor originally formulated by geneticist Sewall Wright in 1932. A technical discussion and retrospective are given in The Adaptive Landscape in Evolutionary Biology, but I will outline the basics below. Evolutionary biologists should feel free to skip the next paragraph.
One way to visualise evolution in action is as a topographic drawing of a mountainous landscape with peaks and valleys, as seen here. The horizontal axes show all possible values for two continuous traits (e.g. body size and wing colour of a butterfly), while the vertical axis shows biological fitness (the odds of contributing offspring to the next generation). Each individual in a population falls somewhere on this graph, depending on its trait values, but not all will contribute equally to the next generation. Those at or near a peak have the best chance of doing so. As this system evolves over multiple generations, you can imagine how this population is pushed towards the nearest peak, natural selection eliminating those individuals in the valleys or plains who are less fit. If this sounds abstract, it could be because their combination of trait values makes them more susceptible to predation.
“the adaptive landscape [is] a powerful metaphor […] to visualise evolution in action”
Those are the basics, but there are some caveats. One is that some peaks are higher than others – some trait combinations bestow more fitness on individuals. What if a population ends up on a suboptimal peak? From the image you can see that, unless you can do it in a single step, you cannot just descend one peak, move through a valley, and up the other peak. Natural selection will eliminate those individuals who “try” (I use quotes here because it is worth remembering that this process is not goal-directed; evolution acts blindly through trial and error, and individuals have no knowledge of where they are on the landscape). How big of a problem that is depends on how many suboptimal peaks there are.
This is where caveat two comes in. See, this image oversimplifies things – an organism’s fitness depends on far more than two, often hundreds of traits. Our poor brains cannot visualise objects with that many dimensions. But you can describe them mathematically and Wagner explains how the number of peaks is astronomically large.
“an organism’s fitness depends on far more than two, often hundreds of traits. Our poor brains cannot visualise objects with that many dimensions.”
So, how does nature get off suboptimal peaks? Biological traits are ultimately coded for by DNA and as biologists know, life has other options to change DNA than single mutations such as genetic drift and recombination. The former is the chance disappearance of certain genes when all individuals carrying it die, something that is statistically much more likely in small populations. The latter is the wholesale exchange of chromosome regions during meiosis, the cell divisions that creates sperm and egg cells. Drift is dangerous and can push whole populations away from fitness peaks and into extinction (this is why conservation biologists are so concerned about habitat fragmentation). Wagner likens recombination to nothing less than teleportation; it allows offspring to take large leaps to a completely different part of an adaptive landscape.
If this all sounds a bit abstract, that is because I am summarising what Wagner lucidly explains in 100 pages and multiple diagrams. It is a daring feat of writing to describe such abstract processes for a general audience. Biologists might shrug: “genetic drift and recombination as sources of new genetic variation – that’s old hat”. Sure, but what is exciting is that Wagner and colleagues are investigating how these mechanisms work in the complex multidimensional sequence spaces he described in his last book. Say what? Last abstract concept, I promise.
“Wagner likens recombination to nothing less than teleportation; it allows offspring to take large leaps to a completely different part of an adaptive landscape.”
The Arrival of the Fittest introduced sequence spaces: the astronomically large number of all possible ways in which you can order a series of DNA bases to form a gene, or a series of amino acids to form a protein. Wagner poetically describes it as:
“a giant realm of possibility […] a library of texts that encodes not only all the countless innovative proteins that evolution has discovered in its history, but also all the proteins that it could discover in the future. It is the space where nature goes to find new parts for its biochemical machines” (p. 40).
Most combinations will be nonsensical, but many will not. Interestingly, Wagner’s computational work suggests that the number of viable genes or proteins encoded by these possibilities is vast. There are many possible solutions to a problem. So many, in fact, that they form networks. Wagner called it a hidden architecture that accelerates life’s ability to innovate. It was an idea that blew my mind back then, and I certainly did not tire reading of it here again, nor of reading how drift and recombination play out in these spaces.
“Wagner poetically describes sequence spaces as the “space where nature goes to find new parts for its biochemical machines””
Midway the book, Wagner completely changes gear. Having covered adaptive landscapes in biology, he asks if this metaphor can have wider use. It can in chemistry, where there are many possible solutions to the problem of arranging atoms or molecules into larger structures. And in computing, such as delivery companies finding the optimal route for their fleet of vehicles. But Wagner even sees parallels in how artists, writers, or composers work, comparing what they do to a form of creative problem-solving in a mental landscape. Here too, finding better solutions sometimes requires big leaps, which can be brought about by play, daydreaming, or other means. Finally, he asks how we can apply these lessons to education, business, and politics to foster more creativity. The second half of the book might not be to everyone’s liking, but I think it is important to take it in the right spirit. Not a grandiose theory, but excited lateral thinking.
As with his previous book, I found Life Finds a Way insanely fascinating. Wagner’s descriptions, in turn poetic or amusing, suggest an author at ease writing about his subject. He has a knack for making abstract, mind-bending concepts comprehensible, though that does not mean the book is not challenging (I reread certain passages multiple times while writing this review to make sure I was describing things right). But when you are reading it, Life Finds a Way feels like an intellectual ride that has sparks flying off it in all directions.
Disclosure: The publisher provided a review copy of this book. The opinion expressed here is my own, however.
Other recommended books mentioned in this review:
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