This is apparently what was happening: Occasionally a virus going about its rounds would accidentally copy one of these innocent “host” genes into its own genome. Passed along from virus to virus, the gene mutated into a form that caused cancer. But all that was a fluke. The virus was an accidental player in the story, the place where the first of these genes happened to have been discovered. Some cancers can be directly caused by a viral invasion—human papillomavirus and cervical cancer, hepatitis viruses and liver cancer. But these are exceptions. Far more often cancer arose when the original gene, sitting secure in its own cell, underwent a random mutation, one caused externally by a carcinogen or internally by an unprovoked copying error. One way or another the gene’s normal function became distorted, tipping the cell toward malignancy. Since genes like these were capable of transmogrifying into a cancer gene, they were named proto-oncogenes. Had their true function been discovered before their aberrant one, they would be called something else.
Studying the genes more closely, researchers discovered how they regulate the ways in which cells grow and multiply in harmony. Some of the genes controlled the production of receptors that protruded from a cell’s surface—molecules tuned to respond to signals from other cells. When these molecular antennae received a message they would relay the information internally to their own cell’s nucleus—instructions to activate the machinery for dividing into daughter cells. If the gene became mutated the cell might produce too many receptors or overly sensitive ones. Spooked into responding to silence, they would pummel the cell with false alarms. Still other broken genes might unleash messages urging the cell’s neighbors to flood it with more growth-stimulating chemicals. Or, in its hyped-up state, the cancer cell might overreact to its own signals, screaming at itself to grow.
Genes related to src are mutated in colon and many other cancers. Crippled ras genes show up in a variety of human malignancies—pancreatic, colorectal, thyroid, melanoma, lung. All that it takes to turn a good ras into a bad ras is a single point mutation—a G flipped to T, A, or C—a random typo in a message hundreds of letters long. Other mutations occur during cellular division when a normal gene is copied too many times. Repeating ras genes are found in lung, ovarian, bladder, and other cancers. Stuttering mycs help give rise to a childhood brain cancer called neuroblastoma. Some mutations are even more wrenching: A chromosome might break and then join with another, placing two previously distant genes side by side. In Burkitt’s lymphoma, a mutation like this shoves a myc gene next to an overbearing stranger that drives its new partner to overexpress itself, churning out signals that cause the cell to divide and divide and divide.
It was a terrifying possibility—that a single mutation might be enough to shift a gene into overdrive and give rise to a deadly tumor. But not even an oncogene wields so much power. Researchers found that inserting one or even two oncogenes into a cell was usually not enough to ignite a cancer—unless the cell had already accumulated some earlier defects. Living systems are governed by a gyroscopic balance in which an extreme force from one direction is met with a countervailing shove. While the 1970s was the decade of the oncogene, in the 1980s scientists began discovering anti-oncogenes—genes whose purpose was to respond to rapid bursts of cellular division by slowing the process down.
Like the proto-oncogenes, these growth-restraining genes were part of a cell’s normal regalia, and they too were discovered when something went wrong. Retinoblastoma is a childhood cancer marked by runaway growth of the light-sensing cells of the eyes. The first sign might be an eerie white glow in the gaze of a child photographed with a camera flash. If noticed early enough the condition can be treated with chemo, radiation, laser surgery, or removal of the eye. If not the outcome can be horrifying, the expanding tumor expelling the eye from its socket. Pictures in nineteenth-century textbooks show the gruesome results, which still occur among the poor in developing countries. The cancer begins when a gene called Rb, short for “retinoblastoma,” has been taken down by a mutation, losing its ability to curb excessive growth.
But Rb, named like so many others because of the accidental circumstances of its discovery, didn’t exist for the sole purpose of suppressing retinoblastoma. Once scientists started looking for Rb genes, they found them throughout the body—and they were missing or crippled in cancers of the bladder, breast, and lung. Unlike an oncogene like myc or ras, growth-restraining genes like Rb are conspicuous by their absence. Because we inherit the chromosomes of both parents, genes exist in pairs. In a single cell, only one oncogene needs to start misbehaving for trouble to begin. With genes like Rb, both copies must be knocked out. If only one is lost the other will still be there to send moderating signals.
Dozens of similarly purposed genes have been discovered: PTEN, apc, vhl, p53—“tumor suppressors,” another awkward name thrust on the world by the human tendency to notice things only when they break. In an old-fashioned radio one can reach in with gloves and remove a hot glowing vacuum tube from its socket, unleashing a blasting squeal from the loudspeaker. Someone coming upon the phenomenon for the first time might name the component a squeal suppressor. But the circuitry is so much more complex. So it is with the suppressor genes. Some produce receptors that listen for inhibitory signals—orders from neighbors to stop overstepping their bounds. Others code for enzymes that muffle the commands of growth-stimulating genes. The rhythm of cellular division is governed by the molecular gears of a cell-cycle clock, and tumor suppressor genes are also involved in the timekeeping.
One of them, p53, sits at the center of a web of chemical pathways controlling the life cycle of a cell. If you want to start a cancer, take down p53. If a cell is damaged and dividing too quickly, external sensors will pick up warning signals from crowded neighbors. Internal sensors will detect chemical imbalances or broken DNA. With an emergency declared, p53 will step in and slow down the clock so that DNA repair can take place. Proofreading enzymes scan the genome. If one strand of DNA’s double helix has been corrupted, the other strand can be used as a template to guide repair. Damaged sections can be excised, a replacement synthesized and put into place.
If DNA repair is broken and other measures cannot save a cell that is mutating beyond control, p53 initiates programmed cell death, or apoptosis. The name is derived from a Greek word describing falling leaves. When an embryo is developing into a little body, it will produce far more cells than it needs. Apoptosis is the means by which it sheds the excess. Webs between fingers and toes are pared back. Lumps of neurons are sculpted into a thinking brain. Apoptosis is not just one big cellular explosion but an intricate procedure in which death signals set off the molecular equivalent of strategically placed depth charges. The nucleus implodes, the cell’s cytoskeleton crumbles. The microscopic remains are engulfed by other cells and a would-be malignancy is gone.
Through random mutations a few cells will learn to thwart or ignore the death signals—and then double and double and double again. A normal cell can divide only fifty or sixty times—a principle called the Hayflick limit. The count is kept by telomeres, caps on the ends of chromosomes that get a little shorter each time around. Once the telomeres fall below a certain size, mitosis comes to a halt and the worn-out cell is taken offline. Cells like those in the immune system, which must divide repeatedly, manufacture telomerase, an enzyme that keeps putting the caps back on the ends of the chromosomes. Cancer cells have also learned this trick, acquiring through the trial and error of mutation the information needed to produce their own telomerase. They can replicate indefinitely.
Conferred with the closest that nature has come to immortality, the cell and its descendants increase exponentially in number, each division giving rise to a new branch of the family tree. The branches divide fractal-like into more branches, and each of these lineages—these many-forking paths—is accumulating mutations. Equipped with different routines and survival skills, the clans compete for dominance.
As this evolution unfolds, the tumor that is
emerging acquires more of the tools of carcinogenesis. Enzymes called proteases eat into healthy tissue. Cell adhesion molecules hold the expanding mass in place. Taking the invasion to a whole new level, signals are sent to healthy cells recruiting them to join the attack. Cells called fibroblasts obediently synthesize proteins for the tumor’s structural support. Endothelial cells—those that line the circulatory and lymphatic systems—are summoned to help make the vessels that nourish the tumor and provide avenues for metastasis. Macrophages and other inflammatory cells, flocking to fight the invasion, are persuaded instead to aid in its expansion—producing substances that stimulate angiogenesis, lymphangiogenesis, and the creation of more malignant tissue. Here lies another paradox of cancer. The panoply of devices normally employed to heal a wound—destroying old diseased tissue and replacing it with healthy new growth—is turned on its head, subverted to promote malignancy.
All of these mechanisms are so intertwined that it can be difficult to tell where one leaves off and another begins. What is being done by the cancer cells and what is being done by its minions? Tumors were once thought of as homogeneous clumps of malignant cells. Now they are compared to bodily organs—systems of interlocking parts. There is a crucial difference. Organs are linked into a network of other organs, each playing an established role. A tumor is attempting to become independent, as though a kidney had decided to break free and set out on a life of its own.
Chapter 6
“How Heart Cells Embrace Their Fate”
In a very creepy way, an embryo is so much like a tumor that the early days of pregnancy resemble the incursion of a malignant growth. Once an egg is fertilized, it travels down the fallopian tube, dividing and dividing along the way. After several days it has become a ball of dozens of identical cells, which proceed to gather themselves into two regions. The outer layer will become the placenta, while the inner cell mass will give rise to the fetus.
Exchanging signals with the uterine wall, this expanding mass, called the blastocyst, prepares to implant itself, the next step in a successful pregnancy. To carve out an opening, protein-dissolving enzymes erode the surface of the uterine lining. As the blastocyst digs in, a process embryologists call invasion, cell adhesion molecules help ensure a tight grip. Normally such an interloper would be rejected as foreign tissue, but messages are sent to the immune system enlisting its cooperation. If all goes as planned, blastocyst becomes embryo, and it begins stimulating angiogenesis—growing vessels to hook into the mother’s blood supply. Every step of the way the molecular interactions of pregnancy are like those that occur during the genesis of a tumor.
As the occupation continues, the cells inside the fetus begin spreading in a well-orchestrated metastasis. First they gather themselves into three layers—the endoderm, mesoderm, and ectoderm (inner, middle, and outer). Cells from each of these primordial regions then strike out on their own, moving into new positions. As they travel they begin to differentiate. Bone and cartilage go here, dermis goes there, with nerves and blood vessels strung through. What began as identical totipotent stem cells—blank slates—become the specific cells of the body. There is no central overseer. Every cell contains the entire genome, and as the diaspora continues genes are turned on or off in different combinations, producing the unique set of proteins that gives a cell its identity. The endodermal cells give rise to the lining of the digestive and respiratory tracts and form the liver, gallbladder, and pancreas. The cells of the mesoderm form muscles, cartilage, bones, spleen, veins, arteries, blood, and heart. The cells of the ectoderm form skin, hair, and nails and also the neural crest, which develops into the nervous system and brain.
While tumors evolve through random mutations, fetuses do so according to a plan. But the deeper biologists look, the more parallels they find. As the fetus develops, tightly connected epithelial cells—the kind that form tissues—must loosen their grip so they can move to new locations. They become wanderers called mesenchymal cells. When they reach their destination they can turn back into epithelial cells and regroup into new tissues. This process, called the epithelial-mesenchymal transition, or EMT, also occurs during healing, when cells are dispatched to repair wounds at distant sites. It seems only natural that cancer would find a way to adopt EMT as a vehicle of metastasis, and there is compelling evidence that it does. Carcinomas, the most common cancers, are derived from epithelial cells. By temporarily changing identity they could more easily disperse through the body. During the transition they might even acquire properties like those of fetal stem cells—the ability to replicate profusely and generate a new tumor. There would be no need for the cancer cell to stumble upon these chameleon talents through random mutations. The program, left over from early days, would be waiting ready-made in the genome like a book forgotten on a shelf. It would simply have to be reread.
Wanting to learn more about the complex processes of life and anti-life, I drove down to Albuquerque one morning where the Society for Developmental Biology was holding its annual meeting. The essence of the science is to tamper with genes that play a role in embryonic unfolding and then see what kind of deformities occur. Experimenting with insects, worms, fish, and other laboratory creatures, biologists are slowly piecing together the steps that lead from a fertilized egg to a fully formed adult. Like ants in amber, the same cellular processes have been preserved and carried through evolution’s forking paths. When activated at the wrong time they can bring on human cancer.
There was a flood of new results to impart since the previous year’s meeting. The only way to accommodate them all was by running sessions simultaneously. “Organogenesis,” “Spatiotemporal Control in Development,” “Branching and Migration,” “Generation of Asymmetry”—a feast of strange, enticing ideas. Darting from one room to another, I could sample the latest reports about the genes directing the development of the liver in the zebrafish or the brain of the sea squirt, or those that ensure that the trachea properly separates from the digestive tract in the embryonic mouse. One could learn about how sex is determined in the worm C. elegans, or how apoptosis—programmed cell death—sculpts the genitals of fruit flies. There were talks about how amphibians and planaria regenerate amputated body parts—and speculation about why that is something mammals cannot do.
Many of the genes directing development were first discovered in fruit flies. When mutated or destroyed, they cause deformations, and so they have been given names like wingless, frizzled, smoothened, patched, and disheveled. Mutations in a gene called hedgehog can cause bristles to grow unexpectedly on the undersides of fruit fly larvae. (A human hedgehog gene is involved in the sprouting of hair from follicles, suggesting possible treatments for baldness.) Genes called snail, slug, and twist are invoked in the gyrations of the epithelial-mesenchymal transition.
As scientists discovered variations, they went even wilder with the nomenclature. Desert hedgehog, Indian hedgehog, and sonic hedgehog. A gene called fringe was soon joined by manic fringe, radical fringe, and lunatic fringe. When mutated during the formation of an embryo the result can be deformities and neonatal cancer. The silly nomenclature has caused some uneasiness among people dealing with the heartbreaking outcome of developmental defects. One medical researcher put it like this: “The quirky sense of humour … often loses much in translation when people facing serious illness or disability are told that they or their child have a mutation in a gene such as Sonic hedgehog, Slug or Pokémon.” The latter, proposed as a name for an oncogene, was withdrawn after the threat of a lawsuit from Nintendo, the maker of the Pokémon game. It now goes by the less evocative name Zbtb7.
No lawsuits were filed by Sega when its video game character, Sonic the Hedgehog, was appropriated by biologists. Even if the company had been inclined to sue, it was soon too late. Since it was discovered in 1993, sonic hedgehog has rapidly emerged as one of the most powerful components of animal development. The first hints came in the 1950s when sheep grazing in the mountains of Idaho were giving birth to deform
ed lambs. In the most hideous cases, there was a single eye in the center of the forehead, and oftentimes the brain had not completely divided into left and right hemispheres. After spending three summers communing with the sheep, a Department of Agriculture scientist discovered the cause. Drought was prodding them to wander higher up the mountains, where they dined on a lily called Veratrum californicum. Laboratory experiments confirmed that pregnant sheep that ate the plant gave birth to cyclopean mutants. The mutagenic chemical was isolated and named cyclopamine. It worked, biologists went on to discover, by suppressing the signals of the sonic hedgehog gene. (Sheep also played a part in the episode of the Odyssey where Odysseus and his men visit the island of the Cyclopes. Trapped in a cave they are devoured, one by one, by the one-eyed monster Polyphemus, until Odysseus blinds him with a homemade spear. He and his soldiers escape by tying themselves to the underside of Polyphemus’s flock.)
In one session after another in Albuquerque, sonic hedgehog was there. It sets in motion a complex molecular cascade—what biologists call the shh signaling pathway—that also involves patched, smoothened, and other genes. In mammals, sonic hedgehog helps establish the left-right symmetry of the body and brain and guides the patterning of the skeleton and nervous system, linking bones with muscle and clothing them with skin. A dose of cyclopamine is not the only way to gum up the works. In the developing embryo, mutations can suppress sonic hedgehog, giving rise to a human deformity called holoprosencephaly. As with the lambs, the baby’s brain doesn’t properly bisect into hemispheres. There may be a nose with a single nostril or a mouth with one instead of two front teeth and, in the most severe cases, a cyclopean eye centered like a headlamp in the face. So many things have to go right during the formation of a child—the proper chemical signals produced, transmitted, and received at the proper locations, in the proper concentrations, at the proper times. More often than we realize, something goes wrong. It has been estimated that as many as one of every 250 early embryos is holoprosencephalic. These pregnancies usually end in a miscarriage, so the defect appears in only about 1 in 16,000 live births. Most of these babies die, but those with milder symptoms can live for years.
The Cancer Chronicles Page 9