Cancer As a Journey Into Our Deep Evolutionary Past – Dr. Khaleel Ashraf

Cancer. The word itself strikes fear, bringing to mind a disease that feels like a betrayal from within. As the world's number-two killer, its a subject of immense research, with over a million papers published in the last fifty years alone. But what if our understanding of cancer is fundamentally flawed? What if this seemingly modern disease is not a chaotic accident of our genes, but a ghost of our evolutionary past, an ancient survival mechanism gone rogue? This perspective, while perhaps surprising, is gaining traction among scientists. It suggests that cancer is not a new invention of damaged cells, but a reversion to an older, more primitive way of life. To truly grasp this idea, we must embark on a journey back in time, over a billion years, to the very dawn of multicellular life.

The Great Evolutionary Leap: From Individualism to Community For a staggering two billion years, life on Earth consisted solely of single-celled organisms. Their imperative was simple and singular: replicate, replicate, replicate. In a sense, these cells were immortal, their existence defined by endless division. But around 1.5 billion years ago, during the Proterozoic epoch, a monumental shift occurred. The first multicellular forms appeared. This transition was a revolutionary step, fundamentally changing the logic of life. To become a part of a larger, more complex organism, cells had to make a profound trade-off. They had to give up their individual immortality. In this new world, immortality was outsourced to specialized "germ cells" (like eggs and sperm) whose sole job was to carry the organism’s genetic heritage forward. The rest of the cells, the "somatic cells" that make up our bodies agreed to a different, mortal fate. They would replicate a limited number of times, perform their function, and then either go dormant (a state called senescence) or commit suicide (apoptosis) for the good of the whole. This was an implicit contract, first signed over a billion years ago. By joining a collective of genetically similar cells, a single cell could ensure the propagation of its genes through the germ line, gaining the survival advantages that a collective body could offer. It was a good deal - it works for us! but like any communal effort, it introduced a vulnerability: cheating. Two quite common misconceptions are that cancer is a ‘modern disease’ and that it primarily afflicts humans. Nothing could be farther from the truth. Cancer or cancer-like phenomena are found in almost all mammals, birds, reptiles, insects and even plants. Work by Athena Aktipis and her collaborators shows the existence of cancer, or cancer analogues, across all metazoan categories, including fungi and corals. Instances of cancer have even been found even in very simple organisms like hydra. The fact that cancer is so widespread among species points to an ancient evolutionary origin. The common ancestor of, say, humans and flies dates back 600 million years, while the broader categories of cancer-susceptible organisms have points of convergence over 1 billion years ago.

The Breakdown of the Contract: When Cells Go Rogue We are familiar with cheating in human society. We pay taxes to support organized government, infrastructure, and defense, but there's always a temptation to dodge those taxes and enjoy the benefits for free. To counter this, governments create layers of rules and enforcement. A similar system exists within our bodies. To ensure cells stick to their part of the multicellular contract, there are layers of regulatory control. A skin cell, a liver cell, or a lung cell will only divide when the organism's rules permit it. If a cell misbehaves or finds itself in the wrong place, the organism's "police" mechanisms will intercede, either preventing division or, if necessary, ordering the cell to self-destruct via apoptosis. But what happens when this policing system fails? What happens when a cell defaults back to its primitive, every-cell-for-itself strategy? It reverts to its most basic, ancient imperative: replicate, replicate, replicate. This uncontrolled proliferation is, at its core, cancer. Cancer, therefore, can be viewed not as a new disease, but as a breakdown of this ancient social contract between somatic cells and the organism.

A New Theory: Cancer as a "Safe Mode" Reboot The conventional explanation for this breakdown is the somatic mutation theory, which posits that genetic damage from aging, chemicals, or radiation accumulates in somatic cells, causing them to go "rogue." According to this view, the hallmarks of cancer—uncontrolled growth, metastasis, evasion of the immune system—are all reinvented anew in each host through a process of fast-paced Darwinian selection. The fittest (or nastiest) cancer cells outbreed their competitors until they eventually kill the host. However, this theory has poor predictive power and struggles with some key paradoxes:  It’s difficult to explain how so many beneficial new functions can arise from damaged and defective genomes in such a short time.  It seems improbable that independent tumors would so consistently acquire the same dozen hallmarks of cancer by chance alone. This has led to a different, more compelling explanation: the atavistic theory of cancer. This theory suggests that cancer cells almost never invent anything new. Instead, they simply appropriate and reactivate already existing functions, many of them very basic and ancient. Think of it like a computer. If it suffers a serious software corruption, it might restart in "safe mode." This is a default program that allows the computer to run on its core functionality, ignoring the more complex bells and whistles that have become damaged. In the same way, cancer is a default state in which a cell under threat reverts to its ancient core functionality, which evolved more than a billion years ago. The hallmarks of cancer are not new inventions; they are re-awakenings of these primitive functions:  Limitless proliferation is the fundamental feature of unicellular life.  Metastasis: the ability to spread to other organs mimics the organized migration of immature cells during early embryogenesis, when they are not yet anchored in place.  Immune evasion and the ability to organize a new blood supply (angiogenesis) are sophisticated survival strategies used by many organisms, from bacteria to early metazoans.

The Evidence in the Genes: Tracing Cancer’s Deep Roots The atavistic theory makes specific and testable predictions. For example, it predicts that the genes causally implicated in cancer (oncogenes) should cluster in age around the onset of multicellularity. Scientists have used a technique called phylostratigraphy to test this hypothesis. This method estimates the ages of genes by comparing them across species, effectively reconstructing a genetic tree of life. The results are striking and support the atavistic theory:  A study in Germany demonstrated a marked peak in cancer genes originating around the time metazoans evolved (around 1 billion years ago).  A recent analysis by David Goode and Anna Trigos in Melbourne found that cancer cells consistently over-express genes belonging to older, unicellular groups and under- express younger genes. As cancer becomes more aggressive, the expression of these older genes increases, confirming that the disease reverses the evolutionary arrow at high speed.  Research by Paul Davies and colleagues found that genes younger than 500 million years were more likely to be mutated in cancer, while genes older than a billion years tended to be protected and suffer fewer mutations. This makes sense if the ancient genes are responsible for running the "safe mode" program. These studies suggest that cancer isn’t just a result of random damage. Instead, it’s a systematic response that activates a very old, deeply embedded toolkit of emergency survival procedures.

The atavistic theory has profound implications for how we approach cancer treatment. If cancer is so deeply integrated into the logic of multicellular life, then a search for a general-purpose "cure" may be an expensive diversion. Trying to eliminate cancer might be like trying to remove a core operating system it's simply not possible without catastrophic consequences for the entire organism. Instead, this perspective suggests that cancer is best managed and controlled. Therapies could be developed to challenge the cancer with physical conditions inimical to its ancient lifestyle. Instead of waging a war of attrition, we might focus on changing the environment, making it a place where the cancer cannot thrive. Furthermore, this new understanding could lead to a new form of early detection. By identifying "informational hallmarks", the subtle activation of these ancient gene networks before any physical tumor is visible, we might be able to detect cancer far earlier and intervene more effectively.

In conclusion, cancer is not a modern disease. It is an ancient, deeply conserved survival mechanism triggered by distress signals. By understanding cancer’s place in the overall context of our evolutionary history, we can shift our focus from a destructive war against our own past to a more intelligent, strategic approach that might finally give us the upper hand against this formidable killer.

References 1. Aktipis, C.A., Bobby, A.M., Jansen, G., et al. (2015). Cancer across the Tree of Life: Cooperation and Cheating in Multicellularity. Philosophical Transactions of the Royal Society B, 370, Article ID: 20140219. https://doi.org/10.1098/rstb.2014.0219 2. Trigos, A.S., et al. (2018). How the Evolution of Multicellularity Set the Stage for Cancer. British Journal of Cancer, 118, 145–152. https://doi.org/10.1038/bjc.2017.398 3. Tomislav Domazet-Lošo, Josip Brajković, Diethard Tautz. (2007). A phylostratigraphy approach to uncover the genomic history of major adaptations in metazoan lineages. Trends in Genetics, 23(11), 533-539. https://doi.org/10.1016/j.tig.2007.08.014 4. Kimberly J. Bussey, Paul C.W. Davies. (2021). Reverting to single-cell biology: The predictions of the atavism theory of cancer. Progress in Biophysics and Molecular Biology, 165, 49-55. https://doi.org/10.1016/j.pbiomolbio.2021.08.002 5. Caporale, L. H. (2012). Overview of the creative genome: effects of genome structure and sequence on the generation of variation and evolution. Annals of the New York Academy of Sciences, 1267, 1-10. https://pubmed.ncbi.nlm.nih.gov/22954209/ 6. Shapiro, J.A. (2011). Evolution: A View from the 21st Century. FT Press. 7. McClintock, B. (1984). The Significance of Responses of the Genome to Challenge. Science. DOI: 10.1126/science.15739260 8. Jablonka, E. (2002). Information: Its Interpretation, Its Inheritance, and Its Sharing. Philosophy of Science, 69(4), 578-605. https://www.cambridge.org/core/journals/philosophy-of-science/article/abs/information- its-interpretation-its-inheritance-and-its- sharing/242A5BBA4808E06DAF43DACE9EFC68BE

Khaleel K. Ashraf, MD, FACP Dr. Khaleel K. Ashraf is a board-certified hematologist and oncologist and a Fellow of the American College of Physicians (FACP). He is a partner at Hematology and Oncology Associates of Alabama, LLC, based in Birmingham, Alabama.