A New Theory on Cancer: What We Know About How It Starts Could All Be Wrong

An Iranian breast cancer patient's mother massages her head after lumpectomy surgery. Behrouz Mehri/AFP/Getty

Paul Davies knows what's wrong with cancer research: too much cash and too little forethought. Despite billions of dollars invested in fighting this disease, it has remained an inscrutable foe. "There is this assumption that you can solve the problem by throwing money at it," he says, "that you can spend your way to a solution." Davies, a theoretical physicist at Arizona State University (ASU)—and therefore somewhat of an interloper in the field of cancer—claims he has a better idea. "I believe you have to think your way to a solution."

Over the course of several years spent pondering cancer, Davies has come up with a radical approach for understanding it. He theorizes that cancer is a return to an earlier time in evolution, before complex organisms emerged. When a person develops cancer, he posits, their cells regress from their current sophisticated and complex state to become more like the single-celled life prevalent a billion years ago.

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But while some researchers are intrigued by the theory that cancer is an evolutionary throwback, or atavism, plenty more think it's silly. That theory suggests that our cells physically revert from their current form—a complex piece in the even more complex puzzle that makes a lung or a kidney or a brain—to a primitive state akin to algae or bacteria, a notion that seems preposterous to many scientists. Yet gradually, evidence is emerging that Davies could be right. If he is—if cancer really is a disease in which our cells act like their single-celled ancestors of eons ago—then the current approach to treatment could be all wrong.

Primordial Stewing

Davies had never considered researching cancer when he received a call from biologist Anna Barker in 2007. At the time, Barker was the deputy director of the National Cancer Institute, and she told Davies about a new initiative there seeking to bring knowledge and insights from the physical sciences—chemistry, geology, physics and the like—into cancer research. The resulting NCI-funded network, which began in 2009 and included 12 institutions, was a chance for cancer outsiders to exchange and expand unconventional insights about the disease. Davies's proposal for a Center for the Convergence of Physical Sciences and Cancer Biology at ASU was selected for the network.

Accustomed to asking the most basic questions in physics—How did the universe begin? How did life begin?—Davies decided to take a similar tack with one of humanity's most feared diseases. He began with two simple inquiries: What is cancer, and why does it exist? Despite decades of research and more than a million scientific papers about the strange, uncontrolled cell growth we call cancer, no one has ever untangled these fundamental mysteries.

For Davies, the first clue about the origin of cancer was the fact that it is common throughout multicellular life; that is, any organism made of several cells rather than just a single cell, such as bacteria. The fact that the disease occurs in so many species indicates that it must have evolved long before humans existed. "Cancer," says Davies, "is very deeply embedded in the way multicellular life is done." In 2014, for example, a German research team led by Thomas Bosch, an evolutionary biologist at Kiel University, discovered cancer in two species of hydra, one of the earliest organisms to evolve out of single-celled primitive species. "Cancer is as old as multicellular life on Earth," Bosch said at the time.

A coloured transmission electron micrograph (TEM) of a cancer cell undergoing mitotic cell division. Getty/Science Photo Library

The evidence that cancer is an evolutionary regression goes beyond the ubiquity of the disease. Tumors, says Davies, act like single-celled organisms. Unlike mammalian cells, for example, cancer cells are not programmed to die, rendering them effectively immortal. Also, tumors can survive with very little oxygen. To Davies and his team, which includes Australian astrobiologist Charles Lineweaver and Kimberly Bussey, a bioinformatics specialist at ASU, that fact supports the idea that cancer emerged somewhere between 1 billion and 1 and a half billion years ago, when the amount of oxygen in the atmosphere was extremely low.

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Tumors also metabolize differently from normal cells. They convert sugar into energy incredibly fast and produce lactic acid, a chemical normally resulting from metabolism that takes place in the absence of oxygen. In other words, cancer cells ferment, and scientists don't know why. This phenomenon is known as the Warburg effect, named for Otto Warburg, a German biochemist who won a Nobel Prize in 1931 for his discoveries about oxygen and metabolism. Up to 80 percent of cancers display the Warburg effect. Researchers know that many cancers depend on the Warburg effect for their survival, but they don't know why. To Davies, the strange way in which tumors metabolize also speaks of cancer's ancient past: They are behaving as if there were no oxygen available.

Malignant cells also produce acid, which Mark Vincent, another proponent of the atavistic theory, says creates an environment reminiscent of the atmosphere during the proterozoic eon, when life first appeared on Earth. The similarity between these two ecologies—inside a tumor and the ancient planet—led Vincent, a medical oncologist at London Regional Cancer Center in Ontario, to wonder if pumping out acid is "a primitive trait" of cancer cells. The fact that cancer cells depend on this vinegary environment for their survival—"[They] can use this acid to eat your body," says Vincent—lends credence to the theory that cancer is an evolutionary regression.

David Goode, computational cancer biologist at Peter MacCallum Cancer Center in Australia, and colleagues found that genes present in single-celled organisms, an indicator of their very old age, were prevalent in the genomes of several cancer types, whereas genes that emerged later were less important for tumor growth and function.

If cancer is a reversal from present to past life form, what triggers the switch? Davies believes the regression begins when the body is damaged or stressed. He uses the analogy of a computer suffering a hardware malfunction and starting up in safe mode. Cancer follows the same pattern—injury followed by single-celled "safe mode"—says Davies, but initiated by, for example, an error in DNA replication instead of a hardware problem. Cancer, says Davies, "is a defense mechanism that has very ancient roots."

The transition of cancer cells from metazoan (animal) to protozoan (single-celled organism) is "not purely an accidental result of random changes," says Goode. Rather, the need to survive drives cancer cells toward a more primitive genome. "Reverting to a more primitive state helps a tumor cell not only divide more quickly, but also adapt to the constant environmental pressures it faces," says Goode.

This view is radically different from the current cancer paradigm, which holds that cancer is a genetic disease. Inherited abnormalities or spontaneous and unpredictable genetic alterations, sometimes caused by environmental carcinogens, produce versions of genes that cause normal operations inside a cell to go awry. Sometimes, a protein responsible for signaling cell division may never shut off. Other times, the signal for cell death never arrives. Researchers have uncovered dozens of pathways gone awry as a result of such genetic variants.

Recent drug development efforts have focused heavily on targeting those pathways to stop cells from dividing, force their death or otherwise halt tumor growth. The results have been mixed. Some of these drugs extend life, such as those targeting the HER2 mutation in breast cancer, the ALK mutation in lung cancer and the BRAF mutation in melanoma.

However, the benefits from so-called targeted therapies have been meager. Although the death rate from cancer fell by about 13 percent between 2004 and 2013, according to the NCI, the overall numbers are still staggering. In 2016, an estimated 1.7 million were diagnosed with cancer and nearly 600,000 people died from the disease in the U.S.

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And the advances have come at a steep cost. Spending on cancer care has more than doubled since 1990, currently exceeding $125 billion per year in the U.S. and expected to reach $173 billion by 2020 . The cost for targeted therapies can easily reach $65,000 per year per patient, but the drugs often extend life by only a few months.

Davies thinks the moneyed and narrow focus on targeted therapeutics is misguided. These new drugs tend to focus on attacking cancer's strengths rather than its weaknesses; its muscle rather than its Achilles' heel. For example, a medication might be designed to stop the abnormal protein that is allowing a cell to divide without stopping. But, says Davies, for as long as cell division has existed, so have threats to it. "Life has had 4 billion years to evolve responses to those threats," he says. Tumors are incredibly adept at circumventing the stress of a new drug by developing genetic abnormalities that preserve their ability to divide. Cancer patients know this strength all too well: Many once-potent therapies stop working because tumor cells become resistant, eventually exhausting all treatment options.

The atavistic theory portends new approaches. Drugging tumors with the lowest possible dose could prevent the evolution of therapy-resistant pathways that would otherwise enable the cancer to spread around the body. "You don't have to get rid of it," says Davies, "you just need to understand it and control it." Vincent envisions exploiting other features of cancer cells, such as the acid environment they produce and their tolerance for hypoxia, or oxygen deficiencies. For example, a drug activated by acid might target cancer cells and not normal tissues.

The Warburg effect could provide another path of attack, by targeting the forces behind cancer cell metabolism, which differs starkly from the normal process. Evidence that cancer is vulnerable to this game plan is mounting. Craig Thompson, the president and CEO of Memorial Sloan-Kettering Cancer Center, recently launched Agios Pharmaceuticals, which is testing drugs against a mutant enzyme that drives metabolism in acute myelogenous leukemia.

Researchers have also been working the oxygen-deficiency angle against tumors. A study in mice with metastatic cancer showed that pure, or hyperbaric, oxygen combined with a diet high in fat and very low in carbohydrates increased survival time. Several studies have also shown a benefit from hyperbaric oxygen therapy. But the initial data are not yet substantial, and the approach is still considered an alternative treatment lacking rigorous clinical evidence. No scientific studies have delved into exploiting the acid environment inside tumors as a treatment. The atavistic theory is too new to have translated into meaningful advances in care.

Radiation therapy for treating lung cancer. Manuel Litran/Paris Match/Getty

Make Room for Novelty

Many oncologists are skeptical that it ever will. Evolutionary biologist Chung-I Wu, at the University of Chicago, calls the atavistic theory "an extreme position." Scientists have also criticized Davies's reference to the discredited "recapitulation theory" that human embryos develop temporary vestigial organs—gills, a tail, a yolk sac—as support for the atavistic model. "I've been ridiculed by the biology community," says Davies.

Genetic analyses by biologist Xionglei He and colleagues, at Sun Yat-sen University, in China, found that the spread of cancer throughout the body occurs when multicellular genes lose their function, stripping away evolved complexity so that tumors resemble single-celled organisms. But in their Nature Communications study, the authors emphasize that cancer cells do not become "a primitive ancestor" from more than 600 million years ago. The notion of "reverse evolution" is, they say, only a general framework, and just one of many layered processes spurring cancer development and growth. Wu cites this work as more "respectable" than the studies by Davies and Vincent.

Davies is unfazed by the objections. "My feeling is, Who cares? The idea was to come in from the outside and lend a fresh perspective," he says. Davies sees the criticism as largely rooted in territoriality and financial concerns. "Cancer is a multibillion-dollar industry that's been running for decades. There's a lot of vested interests out there." After five years with the NCI program, Davies is now funded by NantWorks, a sprawling private health care company owned by scientist and billionaire investor Patrick Soon-Shiong (who made his fortune reworking the breast cancer drug paclitaxel to be more effective) to continue his work developing the atavistic model.

Mark Ratain, an oncologist focused on new drug treatments at the University of Chicago, points out that most current therapies are too toxic, too expensive, and aren't making real headway. Ratain recently started a nonprofit, Value in Cancer Care Consortium, to test new drug regimens that would reduce the cost of cancer care. "We have to make room for novel drugs," says Ratain, "and novel ideas."

Vincent, who had his first atavism insight at around the same time as Davies, is also pursuing the theory. Vincent takes the single-celled phenomenon one step further, believing that cancer could be its own species. The stark difference between our healthy cells and cancerous ones looks more like a jump across the evolutionary tree rather than a hop to another branch. "It seems to me to be a different form of life," he says. Vincent acknowledges that DNA mutations often cause cancer, but he sees the genetic paradigm as "very incomplete."

Regardless of whether the atavism paradigm eventually improves patients' lives, many experts see value in breaking mental barriers surrounding cancer. "Oncologists like me have failed," says David Agus, who directs the Lawrence J. Ellison Institute For Transformative Medicine at the University of Southern California and co-authored a paper with Davies about the need for new insights about cancer. "We haven't really made that much of an impact against this horrible disease." Davies thinks the future of cancer could depend on this ancient view. "The truth is," he says, "I think we're onto something."