The Cancer Chronicles (19 page)

As I pondered what counts as a blockbuster drug, the auditorium was aroused by a fanfare of strings. This was a first for me—a scientific meeting with its own musical theme.
Harold Varmus, the director of the
National Cancer Institute, was taking the stage. To accommodate an audience of thousands of people, each speaker’s image was projected on six sets of double screens—one half for the video of the lectern and the other for PowerPoint slides. The images loomed so large that the speaker himself, off in the distance, appeared comically small, the man behind the curtain in
The Wizard of Oz.
Varmus began with the good news: Overall
incidence and mortality
rates were continuing to inch a little lower every year.
That, of course, is after adjusting for the aging of the population. The frightening reality, he reminded everyone, is that wave after wave of baby boomers are entering their sixties and seventies—prime
cancer time. Even with a modest decline in the amount of cancer per capita, the sheer number of cases will soar. At the same time government research funding was not even keeping up with inflation. “We’re not just poor but living in a land of uncertainty,” Varmus lamented.

Watching these lavish presentations with their state-of-the-art audiovisual enhancements, I found it hard to think of cancer as medicine’s neglected stepchild. All medical research has been threatened by budget cuts. But when you add to the government grants the
money that is going toward pharmaceutical research (the justification given for those five-figure drug price tags) and the private dollars raised in telethons and donated by the wealthy hoping to stave off their own death or to memorialize a loved one with a new medical center wing, great resources were going toward understanding cancer in the minutest detail. Would billions of additional dollars soon lead to the drugs, always just beyond the horizon, that would zero in on advanced-stage cancer without the collateral damage of chemo and radiation, buying not just weeks or months but an actual cure? Would death rates fall
as precipitously as they have for heart disease? Would people stop lamenting that we are
losing the War on Cancer?

There is so much money to be made in the fight, and I was taken aback by how many top university researchers had a hand in the commercial world.
Elizabeth Blackburn, who was stepping down as president of AACR, had won a
Nobel Prize for her research on
telomeres and
telomerase. She was also a
founder and chairman of the advisory board of an enterprise called
Telome Health, Inc. Throughout the week every presentation began with an obligatory slide disclosing any conflicts of interest. There was clearly some resentment over the requirement. Some speakers flashed the words so quickly that they were impossible to read. I was reminded of those television car commercials where a comically sped up voice rapidly spews out
the fine print and disclaimers. One plenary speaker hurriedly
said that she had lost her slide. (It would have indicated that she and her husband were cofounders of a publicly traded pharmaceutical company that is developing targeted
cancer therapies.) Other speakers proudly declared, often to applause, that they had nothing to disclose, and one said that his biggest conflict of interest was that for twenty-five years he had worked on a skin cancer treatment “and therefore
I really want this stuff to work.”

Varmus is one of the giants of medical science, sharing his own
Nobel Prize with
J. Michael Bishop for their
pioneering work on
viruses and
oncogenes. He seemed glad to get money matters out of the way so he could move on to the science and
some of the most perplexing questions it faced: Why is it that some cancers—testicular, for example, and some
leukemias and
lymphomas—can be killed by chemo alone while others are stubbornly
resistant? What are the biological mechanisms that account for obese people having a higher cancer risk? Why do patients with
neurodegenerative diseases like
Parkinson’s,
Huntington’s,
Alzheimer’s, and
fragile X appear to be at lower risk for most cancers? Why do the body’s tissues differ so dramatically in their tendency to develop cancer? As I listened, it occurred to me that I had never heard of
cancer of the heart. (It does occur but is extremely
rare.)

For the rest of the morning other luminaries stepped forth to speak about the future, each preceded by the rousing melodic fanfare and the disclaimer slide. With the latest technology researchers are sequencing the
genomes of cancer cells, far more rapidly than had seemed possible even a few years ago. By comparing the tumor genomes with those of normal cells, they are seeing on a finer grain than ever the
mutations that can produce a malignancy. Some of
the results have been surprising. According to the common wisdom it typically takes half a dozen or so damaged genes to tip a cell. But two cases of the same kind of cancer (breast cancer, say, or colon cancer) needn’t arise through the same combination of genetic alterations. Genomics research suggests that for some cancers dozens
and even
hundreds of mutations may potentially be involved. Of the approximately 25,000 genes in the human genome, at least 350 have been identified as possible
cancer genes—ones that can be altered in a way that confers a competitive advantage. According to some predictions, the number may eventually run into the thousands.

“Cancer is not a disease. It’s a hundred different diseases”—how many times has that been said? Now the talk is of cancer as tens of thousands of diseases each with its own molecular signature. One day, as these technologies develop, scientists may be able to routinely analyze the unique characteristics of every individual cancer and provide each patient with a personally crafted therapy. It is a lot to hope for.

We left the auditorium, the thousands of us, and diffused throughout the cavernous spaces of the convention center. Every lecture room and every corridor of posters offered more elaborations on the cancer theme. There was
the phenomenon of
polarization—the way a healthy cell can tell its front from its back. This allows epithelial cells to orient themselves within a tissue so that hair, scales, and feathers all lean the same way. During
mitosis a cell must polarize, portioning out its contents before it splits into two identical cells. A migrating cell is exhibiting polarization when it transports its proteins in a way that keeps it moving forward and not backward, as though riding on its own conveyor belt. Some of the molecular circuits involved in polarization have been uncovered, and in a cancer cell they are among the things that can go askew. Whether that is a symptom or a cause of the malignancy is another of the unknowns.

While that
question was being pondered, researchers in another room were discussing
the many different kinds of cell death. Switching off
apoptosis is an established hallmark of cancer, and
chemotherapy typically works by forcing apoptosis back on. But there are also
autophagy (the cell eats its own insides),
entosis (a cell cannibalizes its neighbor), and
necroptosis, which like apoptosis involves
molecules called death
receptors and RIPs (the epitaph stands for “receptor-interacting protein”). Maybe these too can be manipulated in controlling
cancer. There is a
Journal of Cell Death,
and a woman in the audience was wearing a black T-shirt with the cryptic words “Cell Death 2009: The Unplugged Tour.” So many little subcultures even in the cancer world.

Other speakers pondered the mystery of why cancer cells change their metabolism from
aerobic to anaerobic, voraciously consuming
glucose in a phenomenon called
the
Warburg effect. This less efficient way to use energy would help them survive in the oxygen-starved reaches deep inside a tumor. But the cells also make this transformation when there is plenty of oxygen available. One reason might be that the altered metabolism allows them to
take in more of the raw material they need to build new parts and proliferate. There were lectures on the ways in which a cancer cell can elude destruction by the
immune system—or turn it to its own uses, attracting
macrophages as allies in the cause.
The slow burn of chronic
inflammation is somehow involved with many
diseases—rheumatoid arthritis, Crohn’s disease,
Alzheimer’s, obesity,
diabetes—and it also plays a role in cancer.
Stomachs inflamed by an immune response to
Helicobacter pylori
bacteria or
livers inflamed by
hepatitis virus are more likely to become cancerous. But how much is cause and how much is effect? The chemical circuitry is still being uncovered. A full session was devoted to the question of how
molecules called
sirtuins, which have been implicated in the aging process, also play a role in inflammation, obesity, and therefore in cancer.

In the end what all of biology comes down to is genes talking to genes—within the cell or from cell to cell—in a constant molecular chatter. I hadn’t considered, however, that the genes in human tissues can also talk to
the genes residing in the microbes that occupy our bodies. Maybe that should have been obvious. Our skin and our digestive and respiratory tracts are teeming with bacteria. Many of them play a symbiotic role—bacteria in the gut secrete enzymes that aid in digestion. The genes inside these single-celled creatures transmit
signals from microbe to microbe, and they can also exchange signals with human cells. Although we think of the bacteria as passengers, they outnumber our own cells by about ten to one. Even more impressive, the total number of microbial genes each of us harbors—the
microbiome—outnumbers our human genes by 100 to 1. There is even
a
Human Microbiome Project to sequence the genomes of these cellular free agents. Cancer is a disease of information, of mixed-up cellular signaling. Now there is another realm to explore.

The genome, the
epigenome, the microbiome—scientists also now speak of the
proteome (the entire set of proteins that can be expressed in a cell) and the
transcriptome (all of the RNA molecules of various sorts). There is the metabolome, lipidome, regulome, allelome … the degradome, enzymome, inflammasome, interactome, operome, pseudogenome.…The exposome is everything in the environment we are exposed to and the behaviorome includes the lifestyle factors that may alter our risk of cancer. The bibliome is the endlessly expanding library of papers on everything scientific, and the curse of this age of microspecialization and the proliferation of “
’
omics” is to
separate the ridiculome from the relevantome.

As I scribbled in my notebook or walked the hallways mulling some strange new idea, I thought of how much has changed over the years in our understanding of cellular biology. I remembered the thrill of reading James Watson’s
The
Double Helix
during a backpacking trip in college and, later on, sitting by the fire in a mountain cabin, devouring the three-part
New Yorker
series excerpted from
Horace Freeland Judson’s magnificent book
The
Eighth Day of Creation: Makers of the Revolution in Biology.
Molecular
genetics seemed as clean and crisp as structures assembled from Lego bricks. For all their power to create and govern life, genes were made from combinations of just four nucleic acid letters: G, C, A, and T. Each had a unique contour, and these patterns of bumps and grooves were copied from DNA to messenger RNA and then ferried to the ribosomes, the cellular structures that used the information to make proteins.
At these foundries other molecules called transfer RNAs acted like adaptor plugs matching each triplet of nucleic acid letters to a particular amino acid—the twenty different units that, arranged in a certain order, became a particular kind of protein. These proteins include the enzymes that help make the genetic machinery run. The crowning simplification of the theory was what
Francis Crick called the “central dogma”: DNA to RNA to protein.

The complications were soon to follow. Not every bit of DNA was part of the protein code. Some sequences were used for making the messenger RNA and transfer RNA. Others served as control knobs, turning the volume of a gene up and down to modulate the production of its protein. With all of this intricate, interlocking machinery, you could almost entertain the fantasy that the whole thing was the product of an engineer. But nature was so much messier. Genes, for example, were not continuous. They were interrupted by scraps of gibberish. As the genetic message was reprinted into the messenger RNA, these blemishes (the
introns) had to be edited out. They were accidents of evolution and of entropy. In fact, of the entire genome only a small percentage appeared to serve a purpose. The rest came to be known as
junk DNA—a hodgepodge of detritus, genes that had become crippled and discarded over the course of millions of years. Some of these pseudogenes had been smuggled in by viruses. Others were created when a real gene was mistakenly copied and pasted elsewhere in the genome. With no compelling reason to get rid of the debris, it was carried along, generation by generation, for the ride.

It seemed barely conceivable that so much of the genome sat silent and inert. In its incessant tinkering, evolution would surely find new purposes for the discarded parts. Early in the 1990s, scientists began to notice a new kind of RNA produced by the junk DNA. When they latched onto a messenger RNA, these molecules kept it from delivering its information. Because of their small size they were named
microRNAs (in the lexicography of cellular biology, terms like this are squished together). They came in different varieties,
and as they increased or decreased in number they regulated the production of various proteins. Like almost everything else in the cell they were bound to play a role in
cancer. Suppose there was a microRNA whose role was to block the expression of a growth-promoting
oncogene. If the cell produced too little of this regulator, that would encourage proliferation. An excess of another kind of microRNA might result in the stifling of a
tumor suppressor. In fact just one of these molecules might regulate several different genes, leading to tangles of entwined effects. Mutations to the junk DNA had been thought to be harmless. But if they upset the balance of microRNAs they could nudge a cell closer to malignancy.