11 The Origins of Life and the Origins of Cancer

ACCUSTOMED TO THINKING about life on other planets, cosmologist Paul Davies wondered how cancer fit into the story of life on Earth. Because cancer is as old as multicellular life itself, the origins of cancer, he reasoned, must lie in the origins of life.

So, let’s take a step back. How did life on Earth evolve?

Life on Earth began an estimated 3.8 billion years ago, perhaps 750 million years after Earth’s formation.¹ Simple organic molecules may have formed spontaneously in Earth’s early atmosphere. Stanley Miller’s famous experiments in the 1950s showed that electrical discharges into a mixture of hydrogen, ammonia, and water that replicated the early atmosphere could produce simple amino acids. But these organic molecules were not yet cells.

The earliest cells were created when self-replicating molecules called ribonucleic acids (RNA) were enveloped in a membrane called a phospholipid bilayer, which is still the basis for all modern human cell membranes. This bilayer protected the RNA from the harsh outside environment, allowing self-replication. These early cells lived in a sea of nutrients, obtaining food and energy directly from their environment. As long as nutrients were available, they survived, but they were always on the edge of extinction.

The prime directive of life, even at this early stage of evolution, was to replicate. Reproduction demands growth, cellular energy generation, and the ability to move around to find more favorable environments. Even viruses, nonsentient pieces of nucleic acids that straddle the border of the definition of life, have a biological imperative to replicate. They may not be fully alive, but they are programmed to replicate and require a host cell’s help to do so.

Prokaryotes are the earliest and simplest organisms that evolved from the primordial soup. It took another 1 billion to 1.5 billion years to evolve the more complex eukaryotes that contained organizing features like a nucleus and organelles. The specialized nucleus carried all the genes necessary for reproduction. Organelles (literally, miniature organs) are subcellular structures that allow the compartmentalization necessary for specific functions such as protein production and energy generation.

The organelle called the mitochondrion generates energy for the cell. Unlike other organelles, mitochondria are believed to have originated as separate prokaryotic cells. As early eukaryotic cells became more complex, mitochondria discovered they could live inside these cells in a mutually beneficial relationship. Mitochondria were protected inside the cell, and in return, they generated energy in the form of adenosine triphosphate (ATP). This relationship evolved over time, and today, one cannot survive without the other. Mitochondria are present in all mammalian cells except for red blood cells.

The mitochondria contain their own distinct DNA, which reflects their origins as separate cells. Although the generation of ATP by oxidative phosphorylation (OxPhos) is considered their main function, mitochondria are also key regulators of apoptosis, a method of controlled cell death.

Early in planet Earth’s history, in the Proterozoic age, the atmosphere was largely devoid of oxygen, and most cells generated energy anaerobically (without oxygen). Earth’s atmosphere began to change with the rise of photosynthetic organisms. Energy from sunlight combined with carbon dioxide to give off oxygen as a waste product, which slowly accumulated in the atmosphere.

This was a big problem for the other early cells, as oxygen is toxic if not handled properly. Our body includes robust antioxidant defenses for precisely this reason. The mitochondria use this oxygen to their advantage by metabolizing glucose through OxPhos. This generated ATP more efficiently but also neutralized some of this toxic oxygen. As a result, present-day mammalian cells have functional pathways for both aerobic (OxPhos) and anaerobic (glycolysis) energy production, and the ratio can vary depending upon energy needs.

The transition from simple prokaryotic cells to the more complex eukaryotic cells, complete with specialized organelles and mitochondria, was a huge evolutionary jump. Protozoans (e.g., yeast) are simple, single-cell eukaryotic cells, but they are vastly more complex and larger than bacteria. All living creatures for the first half of the history of life on Earth were single-cell organisms. The next big evolutionary hurdle was multicellularity.

THE JUMP TO MULTICELLULARITY

Single-cell organisms are selfish creatures; they live, grow, breed, and pretty much do everything else by themselves. There is nobody for them to help out and nobody to help them. Their prime directive is their own survival and reproduction. To be successful, a single-cell organism competes with surrounding cells for resources. But cells working together have a huge advantage over cells working alone.

Multicell organisms evolved about 1.7 billion years ago, likely beginning as simple aggregates or colonies of single-cell eukaryotes. Over time, mutually beneficial collaboration between cells permitted specialization, which then led to true multicellular organisms. Specialization, division of labor, and intercellular communication made these organisms bigger, more complex, and more capable than simpler single-cell organisms. The human body contains more than two hundred types of these specialized cells, which are broadly classified into five categories: epithelial tissue, connective tissue, blood, nervous tissue, and muscle.

But this new complexity demanded new rules of multicellular cooperation. When grouped together, individual cells must learn to live and work together just as individual people in large cities do. A single-cell organism is like an individual living alone in the woods. He may do whatever he likes; nobody else is around to care. He can walk around naked all day if he wants. Multicell organisms are like large, densely populated cities. There must be rules to govern acceptable behaviors. A man walking around naked may be arrested. The needs of the many outweigh the needs of the individual. In return for the sacrifice of a few individual freedoms, societies allow specialization, division of labor, and communication. This increased complexity allows cities and nations to dominate their environment.

A multiperson city or a multicell organism prioritizes decisions to benefit the collective. In a city, some individuals die so that others benefit, such as soldiers, firefighters, and policemen. In a multicell organism, cells such as the white blood cells of the immune system may be sacrificed for the good of the many cells within the entire organism.

Cells must follow strict rules for cooperation and coordination if they are to live and work together. The priority for single-cell versus multicell organisms changes significantly. Single-cell organisms compete with other cells to benefit themselves. Multicell organisms cooperate with other cells to benefit the entire collective of cells that make up the organism.

Multicell organisms compete with other organisms for food, but at a cellular level, all the cells within that organism cooperate (see Figure 11.1).

Figure 11.1

These cell-level differences between single-cell and multicell organisms manifest in several important ways: growth, immortality, movement, and glycolysis.

Growth

Single-cell organisms grow and replicate at all costs. That is their entire purpose in life, and their default state. A bacterium in a Petri dish or yeast in a slice of bread never stops trying to grow and reproduce. It does not stop until resources run out.

By contrast, multicellular organisms impose tight control over growth using genes that promote growth (oncogenes) and genes that suppress it (tumor suppressor genes). Cells may grow only when they are told—in the right place and at the right time. A liver cell cannot grow on the tip of your nose. Also, liver cells cannot grow to the size of a refrigerator; this would impact the lung, living right next door. Good fences make good neighbors. This ensures the well-being of the entire organism, not the individual cell.

Similarly, the single person and the multiperson city differ substantially in their approach to growth. The lone survivalist in the woods faces no restrictions on growth. He may build his house as large as he wants, and wherever he wants. Growth is generally good. Cities, by contrast, impose tight control over growth. You cannot simply build a shed on your neighbor’s property. There are rules that ensure cooperation. Growth is generally bad because there is limited space available. If you grow, it will be at your neighbor’s expense. Growth of the whole city is good, but growth of the people within that city is bad if the city itself is not expanding.

Immortality

Single-cell organisms are immortal because they can replicate infinitely. There is no limit to how many times a single-cell organism like yeast can divide. For example, there are sourdough yeast starters that are more than a hundred years old that are still used to make bread.² The yeast grows and replicates indefinitely as long as conditions are right. The yeast line is immortal.

Cell lines in a multicellular organism are not allowed to live forever. Each time they replicate, their telomeres get a little shorter, and when they are at a critical length, the cells can no longer divide. At that point, the cell line has reached senescence. Decrepit cells that have divided too many times are condemned to die through apoptosis. Once they have outlived their useful lives, they are removed for the good of the organism.

A lone survivalist in the woods may keep his house as long as he wants, even if the roof leaks and the walls are about to fall down. In a city, when houses get too old, they are condemned and destroyed so that other people do not get hurt. The needs of the many take precedence over the needs of the individual.

Movement

Movement is the natural state of single-cell organisms. They have no particular obligation to stay in any specific place. They move around to find the most favorable environment. Bacteria have evolved to move in many spectacular ways. Some bacteria use an organelle called a flagellum, a long structure that acts much like a propeller. Other bacteria use twitching and gliding movements made possible by an organelle called a Type IV pilus.

Single-cell organisms also take advantage of passive movement. For example, when conditions are unfavorable, yeast enters a dormant state called a spore, which can be picked up and scattered by the wind. Some will find a favorable growth environment, reactivate, and bloom. Others will not, and will continue to lie dormant. Baker’s yeast, for example, may stay in the little plastic packet for years and still reactivate when placed in warm water.

Movement is particularly advantageous to single-cell organisms’ survival because they depend so heavily on their environment to provide for their needs. Yeast that stays in the same location for too long may exhaust its resources and perish. Being able to move means it can find more abundant resources elsewhere to thrive and reproduce.

By contrast, multicellular organisms must ensure that their cells remain anchored to their proper location and don’t move around. Cells interact and depend on one another, so they must be in the right place at the right time. The liver depends upon the lung cell to gather oxygen, and the rest of the body depends on the liver to detoxify the blood. For this to work, everybody must be in the right position. The lung cell can’t just hop into the bloodstream and take a ride downtown to hang out with the liver. Multicellular organisms have evolved complex systems called adhesion molecules to attach cells to their proper position.

The default state of single-cell organisms is movement, and the default state of cells with a multicell organism is staying put (stasis). Movement occurs at the level of the entire organism, not at the level of the individual cell. Organisms move around, but the cells within that organism do not.

A man living alone in the wilderness may move around wherever he wants. If conditions are good in one spot, he may stay. If not, he may move to a better location. Early human tribes were often nomadic, roaming the countryside looking for food and evading enemies. But a man living in New York City cannot simply move wherever he wants. He can’t just walk into another person’s house. This is one of the many rules of living in a society.

Glycolysis

Energy generation evolved in three stages: glycolysis, photosynthesis, and oxidative metabolism.

Earth’s early atmosphere was largely devoid of oxygen (anaerobic conditions), and thus the earliest evolved form of energy generation was glycolysis. This process breaks down a glucose molecule for two ATP and two lactic acid molecules and does not require oxygen. All modern human cells have the capacity to undergo glycolysis.

The next major evolutionary step in energy conversion was photosynthesis, which arose approximately three billion years ago. Proliferation of photosynthetic bacteria caused rising atmospheric accumulation of oxygen.

The increased availability of oxygen set the stage for the evolution of the third major type of energy generation: oxidative phosphorylation, or OxPhos, using the mitochondrion. OxPhos burns glucose with oxygen to provide thirty-six ATP per glucose, a massive upgrade from the two ATP produced by glycolysis. OxPhos is almost universally used in modern human cells when oxygen is available. While most single-cell organisms use the more primitive glycolysis, most eukaryotic cells use OxPhos.

So, to summarize, single-cell organisms differ from multicell organisms by these following four main characteristics:

They grow.
They are immortal.
They move around.
They use glycolysis (also called the Warburg effect).

Does this list look familiar? It should; this is precisely the same list of attributes that make up the four hallmarks of cancer! (See Figure 11.2.) Surely this is not a coincidence. The hallmarks of cancer are also the hallmarks of unicellularity. Cancers are derived from cells that are part of a multicellular organism, but their behavior closely resembles that of a single-cell organism.

Figure 11.2

Cancer cells differ from normal cells precisely in the way that single-cell organisms differ from cells within a multicell organism. It’s like the answer to a college SAT question: cancer cells are to normal cells as single-cell organisms are to cells in a multicell organism. Considered from this vantage, we can see even more similarities between cancer cells and single-cell organisms.

SPECIALIZATION

A person living alone in the forest must perform all the tasks of survival: gathering food, hunting, protecting himself, sewing clothes, etc. He does not live long if his only skill is performing tax audits. A society enables people to specialize: farmers, hunters, bakers, merchants, etc. Cooperation and coordination permit greater efficiency, and this increased complexity eventually allowed humans to reach outer space, build supercomputers, and conquer the atom. But these benefits of specialization come at the cost of other functions.

Single-cell organisms can rely on only themselves to perform all the functions necessary for life, and therefore cannot specialize to perform a single function. Microscopic descriptions of cancer cells characterize them as primitive or dedifferentiated (less specialized). As cancer progresses, cells become more primitive in appearance, with progressive loss of “higher” specialized functions. The term anaplasia—derived from the Greek ana, meaning “backward,” and plasis, meaning “formation”—is often applied to cancerous cells. Cancer cells seem to be moving backward in evolution.

This is most obvious in blood cancers such as acute myelogenous leukemia (AML). Normal bone marrow produces immature white and red blood cells called blasts. When mature, they are released into the bloodstream. These blasts normally constitute less than 5 percent of the bone marrow and are not found in the bloodstream. AML is defined by the presence of more than 20 percent of these immature blast cells in the bone marrow. They are often also found in the bloodstream, an ominous sign. Cancerous progression is the move toward less developed, more primitive, and less specialized cellular forms.

Cancer shifts away from specialized function and toward pure reproduction and growth. Normal breast cells are specialized to make milk when needed. A breast cancer cell, for its part, is not primarily concerned with milk production, but with growth of more breast cancer cells. A colon cancer cell no longer concerns itself with absorption of nutrients, but is concerned mainly with its own growth and replication.

By contrast, multicellularity allows division of labor and specialization in structure and function. This increased size and complexity allow it to dominate its environment. Liver cells are specialized to function with much higher efficiency. But they become so specialized that they cannot survive alone. You can put some bacteria on the ground, and they may flourish. But put a piece of liver onto the ground, and it will certainly die.

AUTONOMY

The lone survivalist in the woods has complete autonomy. The man who lives in New York City must follow many rules and laws. He must pay his taxes. He must follow his condominium’s code of conduct. He must adhere to societal norms.

Single-cell organisms are their own boss, with complete autonomy. Cancer cells are the same; they do not follow the rules. Breast cancer cells will not respect the borders of the breast, but will metastasize to other organs. Breast cancer cells do not respond to orders from the brain or hormones or any of the other normal controlling methods the body uses. Breast cancer cells grow for their own good, not the good of the organism.

In multicellular organisms, individual cells must do exactly as they are told. Hormones carry detailed instructions on what to do. If the hormone insulin is high, then cells cannot refuse entry to glucose. They have no autonomy. Cells have no existence outside the whole organism. Your lung doesn’t rummage around in the refrigerator at night. We don’t stop to say hi to our neighbor’s liver while out walking the dog. You don’t yell at your kidney to put the toilet seat down.

HOST DESTRUCTION

The lone survivalist may or may not care for his surrounding environment. He may dump garbage in the river, to be carried away and become somebody else’s problem. A city, however, carefully regulates the local environment. Garbage must be deposited in certain places. You do not drive on your neighbor’s carefully manicured lawn.

Single-cell organisms take no responsibility for the environment around them. A yeast will do whatever it can to kill its bacterial neighbors, because they are competition for food and other resources. Sir Alexander Fleming observed the penicillium mold secrete a substance that killed all surrounding bacteria. This led to the discovery of the world’s first modern antibiotic, penicillin.

Cancer cells, like unicellular organisms, are locally destructive. A cancer will grow at the expense of its neighbors, destroying any surrounding tissue. The worse it is for its neighbors, the better it probably is for the cancer. Cancer is the guy who deliberately drives his pickup truck over his neighbor’s lawn. Competition can involve making yourself better or making your competitors worse. Both strategies work. Welcome to the jungle.

As in a society, cells in a multicellular organism must be good neighbors. Multicellular organisms must maintain the extracellular environment (called the extracellular matrix) so as not to harm their neighbors. Normal liver cells, for example, cannot simply dump their waste next door into the lung’s backyard. Normal breast cells can’t start destroying neighboring skin cells.

EXPONENTIAL GROWTH

Single-cell organisms grow by dividing into two daughter cells. With sufficient resources, the population doubles with each generation, resulting in very rapid exponential growth. This exponential growth is typical of cancer but not of cells in multicellular animals. The adult liver, for example stays roughly the same size because the millions of new liver cells being created are balanced by an equal number of dying cells. As noted previously, multicell organisms maintain tight control over growth, not allowing unbridled population expansion.

INVASION INTO NOVEL ENVIRONMENTS

Single-cell organisms often invade and exploit new environments in their unending search for more food. Yeast mold growing on a slice of bread will continue spreading until it covers the entire slice.

Cancer, like single-cell organisms, invades everywhere and can colonize new environments in the process of metastasis. Breast cancer cells can survive in the liver. Lung cancer cells can survive in the brain. Infections, too, are often said to metastasize. An infection may start in the kidneys, spread through the bloodstream, and infect the heart valves. These metastatic infections are commonly lethal, too.

Cells within multicellular organisms maintain clear boundaries; they cannot survive outside their designated areas. A normal breast cell cannot survive in the liver, a completely foreign environment. A lung cell cannot survive in the brain.

COMPETITION FOR RESOURCES

Single-cell organisms compete vigorously for resources. It’s every bacterium for itself. Cells that grab enough food will survive to reproduce. Those that do not will die. Cancer similarly competes for resources directly, with no thought for the ultimate good of anybody else. A cancer cell will use all the glucose it can, even if it must deprive normal cells. Cancer patients often lose extreme amounts of muscle and fat, as the cancer gorges itself. This process, common in most advanced cancers, is called cancer cachexia.

Cells in multicellular organisms do not directly compete with one another for resources such as glucose. When resources are scarce, there are clear rules for division. For example, during times of starvation, menstruation and reproductive ability are suspended, hair production slows, and fingernails become brittle. Scarce resources are directed toward survival of the organism, and some individual cells may be sacrificed. Relatively superfluous cells undergo apoptosis.

GENOMIC INSTABILITY

Genetic variation allows a species to evolve and survive in unpredictable environments. Single-cell organisms reproduce asexually, splitting into two daughter cells that are genetically identical to the parent. If the genes are reproduced with 100 percent fidelity, there will be no genetic variation whatsoever. To create genetic diversity, single-cell organisms must mutate.

Microorganisms often elevate their rate of genetic mutation in response to stress using complex mechanisms such as aneuploidy,³ slipped-strand mispairing, polymerase slippage, gene amplification, deregulation of mismatch repair, and recombination between imprecise homologies.⁴ These processes sound complex because they are. The point is that necessity is the mother of invention: single-cell organisms find ways to increase mutation rates when needed.

Cancer, as has been painstakingly noted, is also full of genetic mutations. Cancer can mutate its genes better than almost anything else in existence. Gene mutation is one of the hallmarks of cancer, a foundational ability that makes cancer . . . well, cancer. For single-cell organisms, and cancer cells, the ability to mutate is a good thing; for multicellular organisms, it is a bad thing.

Multicellular organisms produce genetic variation by reproducing sexually, which mixes parental genes, but even when different sets of genes are combined, genomic stability is favored. Cells are so highly interdependent that a mutation in one cell will usually adversely affect another. If a lung cell mutates and no longer functions, it will adversely affect the rest of the body. A mutation in one hormonal pathway will likely impair another and have a domino effect. Thus, multicellular organisms evolved DNA-repair mechanisms to slow this natural mutation rate.

Mutations allow unicellular organisms to develop genetic variation to deal with environmental instability. Cells in a multicellular organism don’t need to deal with environmental instability, because conditions are held relatively static. The ionic composition of the surrounding fluid is held within very tight limits. Body temperature is relatively constant (see Figure 11.3).

Figure 11.3

Figure 11.4

This paradigm of cancer as an invasive protozoan explains why cancer resembles an infection much more closely than other human diseases such as heart disease.

THE EVOLUTIONARY PARADIGM

Cancer originates from cells of a multicell organism, but it behaves precisely as a single-cell organism. This is a spectacular and novel finding. At long last, we have a new answer to the age-old question: what is cancer? The conventional answer from cancer paradigm 2.0 had long been that cancer is a cell with randomly accumulated genetic mutations. But Davies and others saw that the origins of cancer lie in the origins of life itself. Cancer is, improbably, a single-cell organism. Multicellular life is about cooperation. Unicellular life is about competition (see Figure 11.4). This type of throwback to an earlier ancestral phenotype is called an atavism, the default to an earlier version, or the return to an evolutionary past.

Human civilization has evolved from small groups of individuals competing with one another to large societies working together. This increased size, complexity, and specialization allow cities to dominate. Similarly, life on earth has evolved from unicellularity to multicellularity. The increased size, complexity, and specialization allow multicell organisms (such as humans) to dominate (see Figure 11.5). Cancer is like the postapocalyptic world of Mad Max, where small bands of people fight one another for resources.

Figure 11.5

The city dweller and the lone survivalist in the woods may appear to be completely different, but really, they are similar, just facing different situations. In the woods, people compete. In the city, people cooperate. But what happens in a city when law and order break down? The city dweller acts more and more like the survivalist. The problem is not only the seed; it’s also the soil.

Cancer is the breakdown of multicellular cooperation. Cancerous transformation happens when a cell in a well-functioning society acts like a single-cell organism. Just as a city has laws in place, normal cells have strong anticancer mechanisms, which include the cells of the immune system. When these are overwhelmed and the rules of cellular cooperation break down, cells must revert to their original programming. As it stops following the rules, cancer will prioritize only its own survival.

Without cooperation, you compete or you die. This reversion toward unicellularity has devastating results for the organism. Because all multicellular life evolved from unicellular organisms, all multicellular life contains the basic pathways needed for cancer. The seeds of cancer are therefore contained within every cell of every multicellular animal. The origins of cancer lie in the origins of multicellular life on earth itself.

But how did that cell, originally part of the multicellular community, change its behavior to that of a single-cell organism? Only one force in the biological universe has that power.

Evolution.