The Cancer Chronicles (27 page)

The projects are done in collaboration with oncologists, and a lot of laboratory benchwork is involved. But there are also attempts to step back further and propose whole new theories of cancer. Cell biology is a science of details. There is a grand overarching framework—the modern theory of evolution—but you excel by digging down and mastering thick layers of knowledge about thousands of biochemical gears and the countless ways they can mesh or jam. There are models for how a neuron fires or how
DNA is translated into protein. But the closer you look, the more elaborate these mechanisms appear. They are the outgrowth of a long chain of evolutionary accidents, a history that might have spun a different way.

Theoretical physics rewards those who simplify—glossing over details and exceptions and explaining everything in terms of a few big ideas. The lumpers instead of the splitters. The last time I saw
Paul Davies, a theoretical physicist and cosmologist, he was speculating on extraterrestrial biology. More recently he and an astrobiologist,
Charles Lineweaver, have been playing with the notion that the human
genome carries inside its coils
an “ancient genetic toolkit”—long buried routines that primitive cells used to form colonies—early precursors to multicellular life. “If you travelled in a time machine back 1 billion years, you would see many clumps of cells resembling modern cancer tumours,” Davies ventured. As they join forces to become a malignancy, cancer cells are reenacting this legacy software, “marching to the beat of an ancient drum, recapitulating a billion-year-old lifestyle.” When earlier traits long dormant in the genome—hen’s teeth, three-toed horse hoofs, vestigial tails in humans—reemerge in later generations, biologists call them atavisms. Cancer, Davies speculates, is an atavistic phenomenon.
Stretching out in another direction, he has suggested that the transition of a healthy cell to a
cancerous one may have something to do with
quantum physics.

It was surprising to see Davies brainstorming about
cancer. Even more unexpected was
Daniel Hillis, a computer scientist and roboticist who is heading a team at the University of Southern California that is assembling
detailed computer simulations of cancer—
virtual tumors—that might be used to predict which drugs work best. I’d first heard of Hillis when as a student at MIT he helped build
a Tinkertoy computer that played tic-tac-toe. He went on to start a company called
Thinking Machines. He may be best known as the designer of
a giant clock that is being assembled inside a mountain in West Texas, where it is supposed to keep running for ten thousand years, chiming through the millennia even if the human race is gone. At a session organized by the NCI he
told an audience of oncologists that the way they were fighting cancer is all wrong—that we need to think of cancer
as a process, not a thing. A body does not have cancer, it is “cancering.” Treatment should focus not on attacking a specific type of tumor in a specific organ but on looking at the patient as a complex system. Somewhere in the network of interlocking parts—the
immune system, the
endocrine system, the nervous system, the circulatory system—something has become unbalanced, and for every patient there may be a different way to set it right. That might have struck some listeners as so much holistic fuzz. But Hillis has been pursuing the idea by building
another of his ambitious machines. Instead of the genome he was
concentrating on the
proteome—all of the proteins that are present in a cell at any one moment. Reading the genome gives you the instructions for making each of the cell’s working parts. Reading the proteome shows which parts are actually being made and in what abundance—a snapshot of the state of the system.

Scientists have been
working for years on mapping the proteome—a formidable task involving laboratory techniques like
liquid chromatography and
mass spectrometry. In collaboration with
David Agus, an
oncologist, Hillis started a company that is trying to automate the multiple steps with a robotic assembly line. Given a drop of blood, the machine extracts and sorts the proteins, arranging them in an image that looks like stars in a sky. Each kind of protein appears as an illuminated spot, and its brightness shows how much there is.

Suppose you have two patients with the same kind of cancer. One responds to a drug and the other does not. Using a device like Hillis’s, you could take their proteomic snapshots and lay one on top of the other and look for something that is different. Even if you don’t know what the pattern means, it might be used as a marker to identify which patients will most likely benefit from the drug. I was reminded of
Henrietta Leavitt, the astronomer who had died of
stomach cancer but not before discovering
Cepheid variables, the pulsating stars
cosmologists use to measure the universe. She would start with two images of the same patch of sky—glass photographic plates taken a few weeks apart. One would be a negative with the stars glowing in black. She would place that plate on top of the other and hold the glass sandwich to the light. Stars that had grown brighter would appear as larger white spots with smaller black centers. On a plate taken weeks later the white spot would have shrunk to its previous size. No one yet knew the physics that caused the stars to blink, but she was able to correlate their rhythm with their distance from the earth. Sometimes our eyes can glimpse connections that our brains don’t understand.

As the population ages, cancer is outrunning us. But placed under this stress we are like those madly replicating
bacteria
Austin talked about—spinning out combinations of memes instead of genes. New ideas. Maybe we really are getting smarter than cancer. Efforts like the
Cancer Genome Atlas are
continually announcing new discoveries—zeroing in on the genetic details of cancers and sorting them into subtypes, each one potentially vulnerable to a different treatment. As the information multiples, custom therapies will be further customized.
Targeted drugs will become ever more precise.
When a tumor finds a workaround, other drugs will be ready to go after the new mutation. Pursuing a different strategy, a new class of pharmaceuticals will switch back on
apoptosis. Immune system
boosters will learn to cleanly distinguish between what is a tumor and what is healthy flesh. A cocktail of these advanced treatments will stop
cancer—even advanced metastatic cancer—in its tracks or manage it indefinitely as a chronic disease. Or maybe in
ten years we will be reading how these approaches too are falling behind in the cellular arms race and we will be forced to look at cancer in an entirely different way.

About a year after he showed me his lab in Princeton, Austin was invited to
Davies’s domain at Arizona State University to give a talk called “
Ten Crazy Ideas About Cancer.” In the end he came up with five, and one in particular has stuck in my mind. It was about
mitochondria. I remembered my surprise when I learned years ago that the mitochondria, these tiny things inside our cells, might once have been bacteria—individual creatures that became trapped somehow. The mitochondria have their own DNA and can replicate independently within the cytoplasm. With their ability to burn
glucose and power the
Krebs cycle—the chemical dynamo that energizes the cell—these symbionts provided their hosts with an evolutionary advantage. They have also long been
suspected of playing a part in cancer. Mutations to the
mitochondrial DNA are found in many different tumors. That might just be collateral damage from the havoc of a cell careening toward malignancy. But there are reasons to think the
mitochondria are more directly involved. For one thing they help
initiate apoptosis, the cellular suicide routine. In his crazy ideas talk, Austin speculated that cancer might begin when the mitochondrial symbionts rebel. From the wear and tear of generating energy, they become damaged and spew out
free radicals that eat at other parts of the cell, including the
genome. The cell gets sicker and the only recourse is to destroy itself. But the mitochondria refuse to cooperate. They don’t want to die. More mutations follow and the cell becomes malignant.

The picture Austin drew reminded me of
A
Wind in the Door,
an allegorical novel by
Madeleine L’Engle in which forces of good and evil contend over the universe. It is a sequel to
A
Wrinkle in Time,
which I discovered as a boy in my junior high school library. It was in L’Engle’s fantasy that I first came across the idea of a
tesseract—a four-dimensional cube. The idea blew my eighth grade mind.
A Wind in the Door
is even stranger. This time Charles
Wallace, the precocious young protagonist, is suffering from a degenerative disease. His mitochondria are gravely wounded, and his microbiologist mother discovers the cause. There are symbionts within the symbionts—the fictional farandolae—and they are rebelling. They are egged on by the
Echthroi, supernatural agents of entropy. Swooping through the universe, they destroy order by what they call
Xing—unnaming things, eating information. Charles Wallace and his sister beat back the demons and after a trip inside a mitochondrion the boy is saved. But in the real world the Echthroi are always with us, stripping off labels, dedifferentiating cells, freeing them to make
cancer.

Early in the spring, a year after the
Relay for Life and a year after the last of
Nancy’s radiation, we traveled to
Patagonia to celebrate. There was a lodge on a lake in the mountains, and for years it had been high on our list of places to see. We wouldn’t be roughing it. Each evening the guests were served fine dinners with good Chilean wines. Our room, through sheer luck, was the best in the house, with a view of both the lake and a waterfall. But the luxury wasn’t the main draw. Each morning we would depart with a group on hiking expeditions to glaciers, mountains, lakes, and rivers. Nancy looked so thin and frail to me, but she made it to the very end of every hike.

One evening after dinner we walked out of the lodge and the stars were more brilliant than we had ever seen. Brilliant and strange. The constellations were unfamiliar, and a pair of dwarf galaxies stared
down at us like two big eyes. It took a minute to realize that they were the
Magellanic Clouds. Magellan had used them to navigate in the Southern Hemisphere, where the North Star is not visible. And it was within these starry nebulae that
Leavitt discovered the
Cepheids. Had she lived in this century, the statisticians tell us, her odds of getting
stomach
cancer would have been much lower. But it still probably would have killed her. With few symptoms at first, it is another of those cancers that is often not noticed until it has
metastasized.
Chemotherapy or
radiation can only hold it in abeyance. For all our understanding of cellular science there is still so much progress to be made. But there are occasionally good surprises. Nancy’s odds hadn’t been good either, and soon she was thriving. Back in Santa Fe she bought a new bicycle and rode in the Santa Fe Century, covering fifty miles.

Every few months she would go to the cancer center for a blood workup. They were keeping their eye on her level of
CA-125,
a protein that is used as a biomarker for the presence of
endometrial and other cancers. Too much CA-125 doesn’t necessarily mean the cancer is back, and you can have cancer without elevated CA-125. It’s
a blunt-edged tool, but in any case Nancy’s remained normal. She also had a
PET scan twice a year, and every time she was clear.

In the fifth year after cancer she bought a horse—something she had wanted to do since she was a girl—and then another horse, and in the sixth year A.C., as she called it, she had fallen in love with two and a half acres of land on the far side of town. It had barns and stables and bordered a square mile of open land. She was determined not to waste a day of a future she had almost lost. It wasn’t an expensive piece of property, and she had inherited a little money after her mother died of breast cancer. So we took out another mortgage and bought the land, and she rode her
horses there whenever she could. We called it the ranch.

I wasn’t a rider but I became obsessed with combating the weeds. There were hordes of the nastiest varieties. In the
gardens at home I confronted an occasional
kochia. Here they were everywhere. Even
worse was a cousin of the weed—
another invader from the Russian steppes—called
Salsola tragus,
or
tumbleweed. Perversely embraced as an icon of the Old West, it first came to South Dakota in the late 1800s possibly from the Ukraine. I imagined it arriving as a seed stuck to an immigrant’s sock. Then it began spreading everywhere. Some farmers thought it was part of a conspiracy and gave it another name, Russian thistle. On the Nevada test range, after aboveground
nuclear explosions were banned, salsola was the first life to come back.

I tried everything but
ionizing radiation to eradicate it. Early in the spring the plants began to appear as tiny bluish-green stars. I learned to recognize them immediately, surgically removing them with a hoe. When that task became overwhelming I burned them with a weed torch. And still they would appear and grow larger, developing ugly lizard-like purple-striped stems. The stems would grow into a tangle bristling with thousands of thorny seeds. A single tumbleweed could have a quarter million of them. I bought a book on weed science and picked the best
chemo—an
herbicide called 3,5,6-trichloro-2-pyridinyloxyacetic acid, or
triclopyr. It was said to break down rapidly in the soil so the environmental impact was low, and it was selective, killing various kinds of weeds but not the native grasses we wanted to encourage. Spray it on a plant and it travels through the phloem and concentrates in the rapidly proliferating cells of the meristem. There it is believed to mimic plant growth hormones called
auxins. Throwing this wrench into the machinery causes the new stems to grow stunted and gnarled, and the plant soon dies. It looks like it is writhing in agony. It was like chemo in reverse, inducing something like cancer. I was careful as I sprayed, in case the fine print was mistaken when it said triclopyr was not a human mutagen or otherwise known to be
carcinogenic. It decomposed rapidly enough that it was not believed to hurt wildlife or to pollute the water table.