Cells That Reverse the Arrow of Evolutionary Time

Fission yeast aka Schizosaccharomyces pombe. Image Source: University of Tübingen.

 
Catastrophic failure or progressive decline? These are alternatives in cellular degeneration. For example, some cells, such as cancer cells, do not age. One commenter at Naked Science Forum notes: "some mutations which cause cancer are not actually causing excessive cell division but a mutation upon the gene which controls programmed cell death... so they don't die when they should and you thus end up with accumulation."

Similarly, researchers have found a type of yeast that does not age (that is, it does not show cellular damage and wear as cells divide over time), but rather, it gets younger as its cells divide. These particular yeast cells do die, but as a result of sudden, catastrophic failure at any given moment, rather than through a progressive decline.

Under favorable conditions, the microbe, a species of yeast called S. pombe, does not age the way other microbes do, the researchers said.

Typically, when single-celled organisms divide in half, one half acquires the majority of older, often damaged cell material, while the other half acquires mostly new cell material.

But in the new study, researchers found that under favorable, nonstressful growing conditions, S. pombe (a single-celled organism) divided in such a way that both halves acquired about equal parts of old cell material. "As both cells get only half of the damaged material, they are both younger than before," study researcher Iva Tolic-Nørrelykke, of the Max Planck Institute of Molecular Cell Biology and Genetics in Germany, said in a statement.

What's more, previous research has shown that when cells divide and continuously pass on old cell material, the cells that get the old material start to divide more slowly — a sign of aging. This has been seen in microorganisms such E. coli and the yeast S. cerevisiae.

But in the new study, S. pombe cells showed no increase in the time it took for them to divide, the researchers said.

That's not to say that S. pombe cells don't die. Some cells did die in the study, but the deaths occurred suddenly, as a result of a catastrophic failure of a cellular process, rather than aging, the researchers said.

The researchers said they are not arguing that any given component of S. pombe cells are immortal. If a particular component of a cell is followed for a long enough time, the researchers believe the cell that harbors this component will eventually die. But "the probability of this death will be constant rather than increasing over time," the researchers wrote in the Sept. 12 issue of the journal Current Biology.

During unfavorable, stressful conditions, S. pombe cells distribute old cell material unevenly, and the cells that inherited the old material eventually died, the study found. Also, during stressful conditions, S. pombe showed an increase in division time.

Although there's no way to know for sure why the researchers did not detect aging in S. pombe under favorable conditions, one likely explanation is that the cellular damage is being repaired at the same rate that it's being formed, said Eric Stewart, a microbiologist at Northeastern University in Boston, who was not involved in the study.

But just because the study researchers did not detect aging in favorable conditions doesn't meant that it's not occurring. "They're trying to show the absence of something," in this case, aging, Stewart said. "Showing the absence of something is a nearly impossible challenge," he said.

S. pombe growth under favorable conditions could potentially serve as a model of nonaging cell types, such as cancer cells, the researchers said.

On the logic of non-ageing cancer cells, I have seen reports that cancer cells are resistant to radiation. Researchers ask: did this condition arise in reaction to radioactive treatments? Or does cancer's radioresistance precede radiation treatments? The conventional wisdom is that cancer involves a genetic predisposition that is triggered by an external factor. Is cancer a body's misguided reaction against radiation, other pollutants in the environment, or viruses? I have seen reports that cancer cells burn sugar, unlike normal cells, which burn oxygen - which is an argument to stop eating sugar if I ever saw one. Is the way cancer works - or the way other non-ageing cells work - the grim key to immortality?

Researcher Paul Davies - author of The Goldilocks Enigma - wrote a 2012 report for The Guardian to ask if cancer is actually a way that a multi-cellular organism can regress to the single-celled organism model, where cells do not seem to age. Thus, he postulates, cancer essentially reverses the normal course of evolution from single cell to multicellular organism, even as the disease reverses the clock on cell death processes. But the question remains: why does cancer do this? What purpose is an evolutionary reversal trying to serve? Davies and an Australian physicist, Charles Lineweaver, maintain that cancer de-evolves a sufferer of the disease at the cellular level. The disease serves to activate increasingly archaic genes in a body as it spreads. Lineweaver claims that cancer is a "default cellular safe mode." From The Guardian report:

In the frantic search for an elusive "cure", few researchers stand back and ask a very basic question: why does cancer exist? What is its place in the grand story of life? Astonishingly, in spite of decades of research, there is no agreed theory of cancer, no explanation for why, inside almost all healthy cells, there lurks a highly efficient cancer subroutine that can be activated by a variety of agents – radiation, chemicals, inflammation and infection.

Cancer, it seems, is embedded in the basic machinery of life, a type of default state that can be triggered by some kind of insult. That suggests it is not a modern aberration but has deep evolutionary roots, a suspicion confirmed by the fact that it is not confined to humans but is widespread among mammals, fish, reptiles and even plants. Scientists have identified genes implicated in cancer that are thought to be hundreds of millions of years old. Clearly, we will fully understand cancer only in the context of biological history.

Two relevant evolutionary transitions stand out. The first occurred over 2 billion years ago, when large, complex cells emerged containing mitochondria – tiny factories that supply energy to the cell. Biologists think mitochondria are the remnants of ancient bacteria. Tellingly, they undergo systematic changes as cancer develops, profoundly altering their chemical and physical properties.

For most of Earth's history, life was confined to single-celled organisms. Over time, however, a new possibility arose. Earth's atmosphere became polluted by a highly toxic and reactive chemical – oxygen – created as a waste product of photosynthesis. Cells evolved ingenious strategies to either avoid the accumulating oxygen or to combat oxidative damage in their innards. But some organisms turned a vice into a virtue and found a way to exploit oxygen as a potent new source of energy. In modern organisms, it is mitochondria that harness this dangerous substance to power the cell.

With the appearance of energised oxygen-guzzling cells, the way lay open for the second major transition relevant to cancer – the emergence of multicellular organisms. This required a drastic change in the basic logic of life. Single cells have one imperative – to go on replicating. In that sense, they are immortal. But in multicelled organisms, ordinary cells have outsourced their immortality to specialised germ cells – sperm and eggs – whose job is to carry genes into future generations. The price that the ordinary cells pay for this contract is death; most replicate for a while, but all are programmed to commit suicide when their use-by date is up, a process known as apoptosis. And apoptosis is also managed by mitochondria.

Cancer involves a breakdown of the covenant between germ cells and the rest. Malignant cells disable apoptosis and make a bid for their own immortality, forming tumours as they start to overpopulate their niches. In this sense, cancer has long been recognised as a throwback to a "selfish cell" era. But recent advances in research permit us to embellish this picture. For example, cancer cells thrive in low-oxygen (even zero-oxygen) conditions, reverting to an earlier, albeit less efficient, form of metabolism known as fermentation.

Biologists are familiar with the fact that organisms may harbour ancient traits that reflect their ancestral past, such as the atavistic tails or supernumerary nipples some people are born with. Evolution necessarily builds on earlier genomes. Sometimes older genetic pathways are not discarded, just silenced. Atavisms result when something disrupts the silencing mechanism.

Charles Lineweaver, of the Australian National University, and I have proposed a theory of cancer based on its ancient evolutionary roots. We think that as cancer progresses in the body it reverses, in a speeded-up manner, the arrow of evolutionary time. Increasing deregulation prompts cancer cells to revert to ever earlier genetic pathways that recapitulate successively earlier ancestral life styles. We predict that the various hallmarks of cancer progression will systematically correlate with the activation of progressively older ancestral genes. The most advanced and malignant cancers recreate aspects of life on Earth before a billion years ago.

Ancient genes remain functional only if they continue to fulfill a biological purpose. In early-stage embryo development, when the basic body plan is laid down (also in low-oxygen conditions, incidentally) ancestral genes help guide developmental processes before being switched off. Every human, for example, possesses tails and gills for a time in the womb. Significantly, researchers have recently identified examples of early-stage embryonic genes being reawakened in cancer.

The deep links between evolutionary biology, developmental biology and cancer have huge implications for therapy, and also provide an unexpected reason to study cancer. By unravelling the details of cancer initiation and progression, scientists can open a window on the past through which we can gain tantalising glimpses of life in a bygone age.

You can see a further article for online from Lineweaver in Physics World at http://www.physicsworld.com/cws/download/jul2013. This is a special issue made free to the public, which deals with the physics of cancer.