A NEW THEORY ON CANCER: WHAT WE KNOW ABOUT HOW IT STARTS COULD ALL BE WRONG

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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.

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.

07_28_Evolution_01A 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.

Read more: Big Genetics and the war over cancer patient data

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.

[Source”indianexpress”]

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