Why We Get Sick (28 page)

O
n March 5, 1992,
The New York Times
carried an obituary for well-known actress Sandy Dennis, a cancer victim at fifty-four. That same day, the eighty-three-year-old actress Katharine Hepburn was enjoying her autobiography’s twenty-fifth week on the
Times’
s best-seller list. An obvious question is, Why did cancer strike Sandy Dennis? What caused her to miss out on the long life that her fellow actress enjoyed?

This obvious question is morally and medically a good one, but there is a more profound biological question: How
is
it possible that any of us can live several decades without dying of cancer? Cancerous cells are merely cells doing their normal thing: growing and proliferating. How could so many cells do such an
abnormal
thing as inhibit their growth for many decades? Obviously they must; otherwise everyone would die of cancer at an early age. This, of course, is the ultimate explanation. Those least likely to die at an early age, from any cause, will be most likely to survive, reproduce, and have their cancer-delaying adaptations at work in future generations. This sort of evolutionary explanation can help us understand the workings and origins of our cancer-preventing adaptations and the prodigious accomplishment they represent.

Confucius once said something like: A common man marvels at uncommon things; a wise man marvels at the commonplace. To marvel at the commonplace of not having cancer and at the mechanisms that make this possible may be the key to understanding how to make cancer even more uncommon.

T
he magnitude of the problem of avoiding cancer may be appreciated from considering the long-term history of any cell in our bodies. A cell now contributing to normal functioning in the liver of some Hollywood star arose by the growth and division of some preexisting cell, probably one closely similar to itself. That parental cell arose from another before that, and so on. As we trace the ancestry of the liver cell, we find cells that look ever less like liver cells and ever more like undifferentiated embryonic cells. Some years back in the cell lineage we come to the fertilized egg from which the entire individual arose.

That cell had a history too, a lineage through various oocytes and oogonia back to the embryonic cells that developed into the Hollywood star’s mother. Likewise, the sperm that did the fertilizing came from a lineage of spermatocytes and spermatogonia back into the embryonic cells of our star’s father. Thus back through the mother’s and father’s original zygotes into the grandparental generation, and so on in endless repetition of ever-dividing embryonic and reproductive cells. Never in these sequences of cell divisions, for the billion years or so since the origin of the first real cells, was there ever one that did not divide, and nowhere in these lineages was there anything that looked like a liver cell.

We offer
Figure 12-1
as an aid in understanding this essential fact of life. All our ancestors had livers, but none of the cells of these ancestral livers gave rise to any of our liver cells, or to anything else in our bodies. We arose entirely from a line of endlessly proliferating germ-line cells. This picture, of an eternal
germ plasm
giving rise to elaborate somata of individuals, which are always genealogical dead ends, was first presented by August Weismann, a nineteenth-century Darwinian.

Now, for the first time in these eternal lines of descent and after dozens of the cell divisions needed to create an adult soma from a single cell, we find a cell, say a liver cell, that must play a specialized role in the life of a multicellular individual. This liver cell must do something none of its ancestors ever attempted: it must stop dividing. If there is an injury to the liver, the cell may be called upon to divide again. This sort of growth and division must be in precisely the
amount and pattern required for normal liver function and must cease as soon as this machinery is fully restored. If ever, in any one of the billions of cells of the liver, the growth and division process is turned on inadvertently and proceeds unchecked, a tumor develops and eventually causes a lethal disruption of some physiological function.

F
IGURE
12-1. Germ plasm concept of Weismann. The eternal line of germ cells gives rise to individual bodies with a limited life span.
The individuals diagrammed can be of either sex.

From this perspective, life seems rather precarious. It suggests that we must have some really superb anticancer mechanisms acting in our favor. As American marine biologist George Liles observed, “the cells and organs that make life possible had better be well designed, because the job of living is formidable. Living beings—plants and animals, bacteria and slime molds and fungi—every animate entity faces a set of challenges that would give pause to the most inventive designer.” He was led to this remark in considering what might seem a rather simple sort of problem, the proper routing of water through the feeding machinery of a mussel. How much more formidable is the challenge of avoiding cancer for several decades in the collection of ten trillion cells that make up a human being!

Biologists today more or less universally believe that multicellular organisms, such as ourselves, arose from some group of the protozoa, in which each cell was a functionally independent individual. Most of their reproduction was asexual, with one cell dividing to form two new ones. In some modern protozoan species these two
new individuals do not break completely apart but stick together in pairs. In others, the offspring of pairs stick together in filaments or sheets called colonies. In a few, the colonies may differentiate into germ cells and somatic cells, as shown in
Figure 12-1
. This means that some previously independent cells, apparently voluntarily, give up reproduction and become genealogical dead ends. They devote themselves entirely to supplying nutrients and protection to the few germ cells that ultimately participate in sexual reproduction. Some such sequence of developmental events, as observed in the much-studied colonial protozoan
Volvox carteri
, must have characterized some remote ancestor of all multicellular animals.

Can this acceptance of a sterile, servile role be explained by natural selection? The answer is obviously
no
, if this process means selection among cells for those best able to survive and reproduce. The answer is
yes
if the selection is among the genes best able to get themselves into future generations. If the reproductive and somatic cells of a
Volvox
colony have the same genes, it does not matter which cells actually do the reproducing and which become sterile. All that matters is that the sterile cells, in their strictly somatic roles, make the colony’s reproduction of genes identical to their own more successful than if they too formed eggs or sperm. If colonies with ten reproductive cells and a hundred sterile ones reproduce more successfully than those with eleven and ninety-nine, the tendency for most of the colony cells to assume a somatic service role will be perpetuated.

A colony of a hundred cells, all derived in a short time from a single original cell, may well be all of about equal health and vigor and will almost certainly be of the same genotype. The resources needed to produce a hundred cells from one may all be shared equally, and all cells have elaborate mechanisms for protecting the genetic material from damage or alteration. But what about a thousand or ten thousand cells? Would colonies that big be asking for trouble? Might there not be occasional mutations that would make cells behave in ways other than those that maximally benefit the colony as a whole? For instance, might not such a mutant cell start appropriating more than its maintenance requirements for nutrients and start growing and reproducing, even though this might be harmful for the colony? Such large colonies surely need special adaptations for maintaining discipline among the many component cells.

H
ow about a colony the size of an adult human body? What sort of special adaptation would be adequate to maintain discipline among ten trillion cells? From an engineering perspective, it is difficult to imagine how any quality control system would be equal to the job. An auto manufacturer faced with turning out a mere ten thousand vehicles, not one of them with a serious flaw, would be well advised to quit the business. A single living cell is incomparably more complicated than any automobile.

Consider the problem faced by an embryo of a hundred cells that gives rise to one of a thousand that produces one of ten thousand and so on to the ten-trillion-cell adult. Most of these cells will die and be replaced by others. All these cells are equipped with genes that turn out products essential to their division, and some genes are adjusted so as to stop making this product when local conditions indicate that the tissue is mature and no additional cells are currently needed. If one of these genes gets accidentally altered in a way that makes it heedless of these conditions and the gene goes on making its product, mechanisms of DNA editing and repair step in and correct the flaw—or at least they are supposed to. One out of about two hundred people has a gene that greatly increases the likelihood of colon cancer. Originally thought to be a gene that actually did something to cause cancer, it is now recognized as a defective form of a normal gene that acts in the detection and rectification of abnormal DNA structure. When this system is not working, DNA abnormalities accumulate and the chance of cancer increases drastically.

Very few such flaws actually get a chance to express themselves. How few? Let’s assume that only one such gene in ten thousand cells makes its product when it is not supposed to. Starting with ten trillion cells, we can assume there are a billion altered cells, scattered through the body, that are capable of initiating a cancerous growth. This is not all that reassuring. But there is another kind of genetic safeguard in each cell: tumor-suppressor genes that actively inhibit cell growth, perhaps by destroying the product of a gene that makes a substance essential to division, when it is inappropriate. Let’s assume that this safeguard is also fantastically effective and that the
daily rate of failure is only one in ten thousand cells. We can now assume we have only a hundred thousand cancers beginning in the body each day. If there were three equally reliable safeguards and abnormal cell division could not begin unless all three failed, there would still be ten new cancer cells formed each day. This is still not very reassuring.

The situation is analogous to the problem of command and control of nuclear missiles. The risk of catastrophe from accidental firing is so great that the system is designed first and foremost to prevent accidental firing, even at the risk of sometimes not being able to fire when needed. This is the exact opposite of the smoke-detector principle we described for defensive responses. Control of cell division could be said to be based on the principle of “multiple safety catches.” The crew in the missile silo cannot fire the missile without a secret code. Even with the code, multiple procedures must be followed in sequence, including two people turning keys simultaneously in two different parts of the room. The system is designed so that any irregularity makes it impossible to fire the missile at all. Similarly, the body’s cells have multiple safety-catch mechanisms. If failure of these mechanisms is detected, other mechanisms stop cell growth. When, despite all previous safeguards, cells grow at an inappropriate rate, still other mechanisms cause the aberrant cells to self-destruct.

A recently discovered gene called p53 is the best example. It makes a protein that protects against cancer by regulating the expression of other genes. In certain circumstances it can shut down cell growth or even make the cell self-destruct. If a person inherits one abnormal copy of the gene that makes this protein, anything that happens to the other copy can lead to catastrophe. The p53 gene is abnormal in fifty-one types of human tumors, including 70 percent of colon cancers, 50 percent of lung cancers, and 40 percent of breast cancers. As John Tooby and Leda Cosmides have pointed out, however, such genetic abnormalities are not necessarily present in the tumor. Cells are often studied after they have lived for years in tissue culture, an environment that may select for genetic abnormalities that increase the rate of cell division.

In addition to these various anticancer mechanisms operating in cells, there are those that operate between them. They detect misbehavior in their neighbors and secrete substances that inhibit the misbehavior. Finally, there is the immune system, which may bring a host of weapons into play against an incipient maladaptive growth as soon
as it finds a difference between it and normal tissue. A detectable cancer must somehow have achieved the highly improbable feat of getting past these many layers of defense. Unlike a parasitic worm or infectious bacterium, it cannot draw on a long history of accumulating its own defenses against the host’s defenses. It is entirely the product of chance alterations in the cellular regulatory machinery. What cancer has on its side is mainly the astronomical number of chances it gets to achieve success against the immense odds.