Tragedy, unfortunately, is the perfect word for it. Heroic figures battling forces greater than themselves. Needless death and destruction. But unlike Greek tragedy, where the Fates predetermine the outcome, the nation's cancer crusade didn't have to play out this way. And it doesn't have to stay this way. Nuclear fission was a mere eight months old when the Panzers rolled into Poland in September 1939, beginning the Second World War. Niels Bohr had announced the discovery at a conference on theoretical physics at George Washington University. Three years later the crash program to build an atomic device from a uranium isotope began in earnest. And within three years of that—Aug. 6, 1945—a bomb named Little Boy exploded over Hiroshima. NASA came into existence on Oct. 1, 1958. Eleven years later, two men were dancing on the moon. Sequencing the entire human genome took just 18 years from the time the idea was born at a small gathering of scientists in Santa Cruz, Calif. Go back as far as Watson and Crick, to the discovery of the structure of DNA, and the feat was still achieved in a mere half-century. Cancer researchers hate such comparisons. Good science, say many, can't be managed. (Well, sure, maybe easy stuff like nuclear physics, rocket science, and genetics—but not cancer.) And to be sure, cancer is a challenge like no other. The reason is that this killer has a truly uncanny ability to change its identity. "The hallmark of a cancer cell is its genetic instability," says Isaiah "Josh" Fidler, professor and chair of the department of cancer biology at Houston's M.D. Anderson Cancer Center. The cell's DNA is not fixed the way a normal cell's is. A normal cell passes on pristine copies of its three-billion-letter code to every next-generation cell. But when a cancer cell divides, it may pass along to its daughters an altered copy of its DNA instructions—and even the slightest change can have giant effects on cell behavior. The consequence, says Fidler, is that while cancer is thought to begin with a single cell that has mutated, the tumors eventually formed are made up of countless cellular cousins, with a variety of quirky traits, living side by side. "That heterogeneity of tumors is the major, major obstacle to easy therapy," he says. Harold Varmus, president of Memorial Sloan-Kettering Cancer Center in New York City, agrees. "I just think this is a very tough set of problems," says Varmus, who has seen those problems from more angles than just about anybody. He shared a Nobel Prize for discovering the first oncogene (a normal gene that when mutated can cause cancer) in 1976. That crucial finding, five years into the War on Cancer, helped establish that cancers are caused by mutated genes. Later Varmus served as NIH director under Bill Clinton, presiding over a period of huge funding increases. "Time always looks shorter in retrospect," he says. "I think, hey, in 30 years mankind went from being almost completely ignorant about how cancer arises to being pretty damn knowledgeable." Yet all that knowledge has come at a price. And there's a strong argument to be made that maybe that price has been too high.
President Nixon devoted exactly 100 words of his 1971 State of the Union speech to proposing "an intensive campaign to find a cure for cancer." The word "war" was never mentioned in the text, yet one would flare up in the months that followed—a lobbying war over how much centralized control the proposed national cancer authority would exert. Between the speech and the signing of the National Cancer Act that December, there was a "battle line between 'creative research' and 'structured research,' " as a news report headlined it. A massive alliance of virtually all the medical societies, the medical schools, the then-Big Three cancer hospitals (Memorial Sloan-Kettering, M.D. Anderson, and Roswell Park in Buffalo) said yes to federal money but wanted very little direction and only loose coordination from Uncle Sam. On the other side was Sidney Farber, the Boston physician known as the godfather of cancer research. He wanted public backing for a massive, coordinated assault. "We cannot wait for full understanding; the 325,000 patients with cancer who are going to die this year cannot wait; nor is it necessary, in order to make great progress in the cure of cancer, for us to have the full solution of all the problems of basic research," Farber testified in congressional hearings that fall. "The history of medicine is replete with examples of cures obtained years, decades, and even centuries before the mechanism of action was understood for these cures—from vaccination, to digitalis, to aspirin." Farber lost. Today the cancer effort is utterly fragmented—so much so that it's nearly impossible to track down where the money to pay for all this research is coming from. But let's try anyway. We begin with the NCI budget. Set by Congress, this year's outlay for fighting cancer is $4.74 billion. Critics have complained that is a mere 3.3% over last year's budget, but Uncle Sam gives prodigiously in other ways too—a fact few seem to realize. The NIH, technically the NCI's parent, will provide an additional $909 million this year for cancer research through the National Institute of Environmental Health Sciences and other little- noticed grant mechanisms. The Department of Veterans Affairs will likely spend just over the $457 million it spent in 2003 for research and prevention programs. The CDC will chip in around $314 million for outreach and education. Even the Pentagon pays for cancer research—offering $249 million this year for nearly 500 peer-reviewed grants to study breast, prostate, and ovarian cancer. Now throw state treasuries into the mix—governors signed 89 cancer-related appropriations from 1997 to 2003—plus the fundraising muscle of cancer charities, cancer centers, and research hospitals, which together will raise some $2 billion this year from generous donors, based on recent tax forms. And finally, that huge spender Big Pharma. The Tufts Center for the Study of Drug Development estimates that drug companies will devote about $7.4 billion, or roughly a quarter of their annual R&D spending, to products for cancer and metabolic and endocrine diseases.
When you add it all up, Americans have spent, through taxes, donations, and private R&D, close to $200 billion, in inflation-adjusted dollars, since 1971. What has that national investment netted so far? Without question, the money has bought us an enormous amount of knowledge, just as Varmus says. Researchers have mapped the human cell's intricate inner circuitry in extraordinary detail, identifying dozens of molecular chains of communication, or "signaling pathways," among various proteins, phosphates, and lipids made by the body. In short, scientists now know (or think they know) nearly all the biochemical steps that a healthy cell uses to multiply, to shut down its growth, and to sense internal damage and die at the right time—as well as many of the genes that encode for these processes. What's more, by extension, they know how these same gene-induced mechanisms go haywire in a cancer cell. According to PubMed, the NCI's online database, the cancer research community has published 1.56 million papers—that's right: 1.56 million!—largely on this circuitry and its related genes in hundreds of journals over the years. Many of the findings are shared at the 100-plus international congresses, symposiums, and conventions held each year. Yet somehow, along the way, something important has gotten lost. The search for knowledge has become an end unto itself rather than the means to an end. And the research has become increasingly narrow, so much so that physician-scientists who want to think systemically about cancer or the organism as a whole—or who might have completely new approaches—often can't get funding. Take, for instance, the NCI's chief funding mechanism, something called an RO1 grant. The grants are generous, averaging $338,000 apiece in 2003. And they are one of the easiest sweepstakes to win: One in three applications is accepted. But the money goes almost entirely to researchers who focus on very specific genetic or molecular mechanisms within the cancer cell or other tissue. The narrower the research niche, it sometimes seems, the greater the rewards the researcher is likely to attain. "The incentives are not aligned with the goals," says Leonard Zwelling, vice president for research administration at M.D. Anderson, voicing the feeling of many. "If the goal is to cure cancer, you don't incentivize people to have little publications." Jean-Pierre Issa, a colleague of Zwelling's who studies leukemias, is equally frustrated by the community's mindset. Still, he admits, the system's lure is powerful. "You get a paper where you change one gene ever so slightly and you have a drastic effect of cancer in the mouse, and that paper gets published in Science or Nature, and in your best journals. That makes your reputation. Then you start getting grants based on that," he says. "Open any major journal and 80% of it is mice or drosophila [fruit flies] or nematodes [worms]. When do you get human studies in there?" Indeed, the cancer community has published an extraordinary 150,855 experimental studies on mice, according to a search of the PubMed database. Guess how many of them have led to treatments for cancer? Very, very few. In fact, if you want to understand where the War on Cancer has gone wrong, the mouse is a pretty good place to start. Outside Eric Lander's office is a narrow, six-foot-high poster. It is an org chart of sorts, a taxonomy, with black lines connecting animal species. The poster's lessons feel almost biblical—it shows, for example, that the zebrafish has much in common with the chicken; that hedgehog and shrew are practically kissing cousins; and that while a human might look more like a macaque than a platypus or a mouse, it ain't that big of a leap, really. The connection, of course, is DNA. Our genomes share much of the same wondrous code of life. And therein lie both the temptation and the frustration inherent in cancer research today. Certain mutated genes cause cells to proliferate uncontrollably, to spread to new tissues where they don't belong, and to refuse to end their lives when they should. That's cancer. So research, as we've said, now revolves around finding first, the molecular mechanisms to which these mutated genes give rise, and second, drugs that can stop them. The strategy sounds obvious—and nobody makes it sound more so than Lander, the charismatic founding director of the Whitehead Institute's Center for Genome Research in Cambridge, Mass., and a leader of the Human Genome Project. The "Prince of Nucleotides," as FORTUNE once called him, sketches the biological route to cancer cures as if he were directing you to the nearest Starbucks: "There are only, pick a number, say, 30,000 genes. They do only a finite number of things. There are only a finite number of mechanisms that cancers have. It's a large number; when I say finite, I don't mean to trivialize it. There may be 100 mechanisms that cancers are using, but 100 is only 100." So, he continues, we need to orchestrate an attack that isolates these mechanisms by knocking out cancer-promoting genes one by one in mice, then test drugs that kill the mutant cells. "These are doable experiments," he says. "Cancers by virtue of having mutations also acquire Achilles' heels. Rational cancer therapies are about finding the Achilles' heel associated with each new mutation in a cancer." The principle is, in all likelihood, dead-on. The process itself, on the other hand, has one heck of an Achilles' heel. And that takes us back to the six-foot poster showing the taxonomy of genomes. A mouse gene may be very similar to a human gene, but the rest of the mouse is very different. The fact that so many cancer researchers seem to forget or ignore this observation when working with "mouse models" in the lab clearly irks Robert Weinberg. A professor of biology at MIT and winner of the National Medal of Science for his discovery of both the first human oncogene and the first tumor-suppressor gene, Weinberg is as no-nonsense as Lander is avuncular. Small and mustachioed, with Hobbit-like fingers, he plops into a brown leather La-Z-Boy that is somehow wedged into the middle of his cramped office, and launches into a lecture:
"One of the most frequently used experimental models of human cancer is to take human cancer cells that are grown in a petri dish, put them in a mouse—in an immunocompromised mouse—allow them to form a tumor, and then expose the resulting xenograft to different kinds of drugs that might be useful in treating people. These are called preclinical models," Weinberg explains. "And it's been well known for more than a decade, maybe two decades, that many of these preclinical human cancer models have very little predictive power in terms of how actual human beings—actual human tumors inside patients—will respond." Despite the genetic and organ-system similarities between a nude mouse and a man in a hospital gown, he says, the two species have key differences in physiology, tissue architecture, metabolic rate, immune system function, molecular signaling, you name it. So the tumors that arise in each, with the same flip of a genetic switch, are vastly different. Says Weinberg: "A fundamental problem which remains to be solved in the whole cancer research effort, in terms of therapies, is that the preclinical models of human cancer, in large part, stink." A few miles away, Bruce Chabner also finds the models lacking. A professor of medicine at Harvard and clinical director at the Massachusetts General Hospital Cancer Center, he explains that for a variety of biological reasons the "instant tumors" that researchers cause in mice simply can't mimic human cancer's most critical and maddening trait, its quick- changing DNA. That characteristic, as we've said, leads to staggering complexity in the most deadly tumors. "If you find a compound that cures hypertension in a mouse, it's going to work in people. We don't know how toxic it will be, but it will probably work," says Chabner, who for many years ran the cancer-treatment division at the NCI. So researchers routinely try the same approach with cancer, "knocking out" (neutralizing) this gene or knocking in that one in a mouse and causing a tumor to appear. "Then they say, 'I've got a model for lung cancer!' Well, it ain't a model for lung cancer, because lung cancer in humans has a hundred mutations," he says. "It looks like the most complicated thing you've ever seen, genetically." Homer Pearce, who once ran cancer research and clinical investigation at Eli Lilly
drug is responsible for side-effects or the combination. "It becomes much more challenging in the context of managing the databases, interpreting the results, and owning the data," adds Lilly's Pearce. Over dinner at Ouisie's Table in Houston, M.D. Anderson's Len Zwelling, who oversees regulatory compliance for the center's 800-plus clinical trials, and his wife, Genie Kleinerman, who is chief of pediatrics there, have no trouble venting about the legal barriers that seem to be growing out of control. It takes no more than ten minutes for Kleinerman to rattle off three stories about trying to bring together different drug companies in clinical trials for kids with cancer. In the first attempt, the trial took so long that the biotech startup with the promising agent went out of business. In the second the lawyers haggled over liability concerns until both companies pulled out. The third, however, was the worst. There were two drugs that together seemed to jolt the immune system into doing a better job of targeting malignant cells of osteosarcoma, a bone cancer that occurs in children. "Working with the lawyers, it was just impossible," she says, "because each side wanted to own the rights to the combination!" Strange as it may seem, much of our failure in fighting cancer—and more important, much of the potential for finally winning this fight—has to do with a definition. Some 2,400 years ago the Greek physician Hippocrates described cancer as a disease that spread out and grabbed on to another part of the body like "the arms of a crab," as he elegantly put it. Similarly, medical textbooks today say cancer begins when the cells of an expanding tumor push through the thin protein "basement" membrane that separates them from another tissue. It's a fancy way of saying that to be cancer, a malignant cell has to invade another part of the body. Michael Sporn, a professor of pharmacology and medicine at Dartmouth Medical School, has two words for this: "Absolute nonsense!" He goes on: "We've been stuck with this definition of what cancer is from 1890. It's what I was taught in medical school: 'It's not cancer until there's invasion.' That's like saying the barn isn't on fire until there are bright red flames coming out of the roof." In fact, cancer begins much earlier than that. And therein lies the best strategy to contain it, believes Sporn, who was recently named an Eminent Scholar by the NCI: Let's aggressively find those embers that have been smoldering in many of us for years—and douse them before they become a full-fledged blaze. Prevent cancer from ever entering that deadly stage of malignancy in the first place. Sporn, who spent more than three decades at the NCI, has been struggling for many years to get fellow researchers to start thinking about cancer not as a state of being (that is, an invasive group of fast-growing cells) but as a process, called carcinogenesis. Cancer, as Sporn tells it, is a multistage disease that goes through various cell transformations and sometimes long periods of latency in its progression. Thus, the trick is to intervene earlier in that process—especially at key points when lesions occur (known to doctors as dysplasias, hyperplasias, and other precancerous cell phases). To do that, the medical community has to break away from the notion that people in an early stage of carcinogenesis are "healthy" and therefore shouldn't be treated. People are not healthy if they're on a path toward cancer. If this seems radical and far-fetched, consider: We've prevented millions of heart attacks and strokes by using the very same strategy. Sporn likes to point out that heart disease doesn't start with the heart attack; it starts way earlier with the elevated blood cholesterol and lipids that cause arterial plaque. So we treat those. Stroke doesn't start with the blood clot in the brain. It starts with hypertension. So we treat it with both lifestyle changes and drugs. "Cardiovascular disease, of course, is nowhere near as complex as cancer is," he says, "but the principle is the same." Adds Sporn: "All these people who are obsessed with cures, cures, cures, and the miraculous cure which is still eluding us, they're being— I hate to use this word, but if you want to look at it pragmatically—they're being selfish by ignoring what could be done in terms of prevention." The amazing thing about this theory—other than how obvious it is—is that we can start applying it right now. Precancerous cell changes mark the progression to many types of solid-tumor cancers; many such changes are relatively easy to find and remove, and others are potentially reversible with current drugs and other treatments. A perfect example is the Pap smear, which detects premalignant changes in the cells of the cervix. That simple procedure, followed by the surgical removal of any lesions, has dropped the incidence and death rates from cervical cancer by 78% and 79%, respectively, since the practice began in the 1950s. In countries where Pap smears aren't done, cervical cancer is a leading killer of women. Same goes for colon cancer. Not every adenomatous polyp in the colon (a lesion in the organ's lining) goes on to become malignant and invasive. But colon cancers have to go through this abnormal step on their way to becoming deadly. The list of other dysplasia- like conditions goes on and on, from Barrett's esophagus (a precursor to cancer there) to hyperkeratosis (head and neck cancers). Obviously, doctors are already doing this kind of testing with some cancers, but they need to do it much, much more. Some complain that the telltale biomarkers of carcinogenesis, while getting more predictive, still are far from definitive, and that we should wait until we know more. (Sound familiar?) Researchers in heart disease, meanwhile, have taken an opposite tack and been far more successful. Neither high cholesterol nor hypertension guarantees future cardiovascular disease, but they're treated anyway. A few cancer researchers have made great strides in finding more early warning signs— looking for protein "signatures" in blood, urine, or even skin swabs that can identify precancerous conditions and very early cancers that are likely to progress. For instance, Lance Liotta, chief of pathology at the NCI, has demonstrated that ovarian cancer can be detected by a high-tech blood test—one that identifies a unique "cluster pattern" of some 70 different proteins in a woman's blood. "We've discovered a previously unknown ocean of markers," he says. And it's potentially a mammoth lifesaver. With current drugs, earlystage ovarian cancer is more than 90% curable; late stage is 75% deadly. Early results on a protein test for pancreatic cancer are promising as well, says Liotta. Yes, the strategy has costs. Some say wholesale testing of biomarkers and early lesions— many of which won't go on to become invasive cancers—would result in a huge burden for the health-care system and lead to a wave of potentially dangerous surgeries to remove things that might never become lethal anyway. But surely the costs of not acting are much greater. Indeed, it is an encouraging sign that Andy von Eschenbach, director of the NCI, and Elias Zerhouni, who leads the NIH, are both believers in this strategy. "What our investment in biomedical research has led us to is understanding cancer as a disease process and the various steps and stages along that pathway—from being very susceptible to it, to the point where you get it, and ultimately suffer and die from it," says von Eschenbach, a former urologist who has survived prostate and a pair of skin cancers. So, he says, he wants to lead the NCI on a "mission to prevent the process from occurring in the first place or detect the occurrence of cancer early enough to eliminate it with less morbidity." There has been talk like this before. But the money to fund the assault never came. And several cancer experts interviewed for this story worry that the new rhetoric from the NCI, while encouraging, has yet to move beyond lip service. For the nation finally to turn the tide in this brutal war, the cancer community must embrace a coordinated assault on this disease. Doctors and scientists now have enough knowledge to do what Sydney Farber hoped they might do 33 years ago: to work as an army, not as individuals fighting on their own. The NCI can begin this transformation right away by drastically changing the way it funds research. It can undo the culture created by the RO1s (the grants that launched a million me-too mouse experiments) by shifting the balance of financing to favor cooperative projects focused on the big picture. The cancer agency already has such funding in place, for endeavors called SPOREs (short for specialized programs of research excellence). These bring together researchers from different disciplines to solve aspects of the cancer puzzle. Even so, funding for individual study awards accounts for a full quarter of the agency's budget and is more than 12 times the money spent on SPORE grants. The agency needs to stop being an automatic teller machine for basic science and instead use the taxpayers' money to marshall a broad assault on this elusive killer—from figuring out how to stop metastasis in its tracks to coming up with testing models that better mimic human response. At the same time, the NCI should commit itself to finding biomarkers that are predictive of cancer development and that, with a simple blood or urine test (like PSA) or an improved molecular imaging technique (PET and CT scans), can give patients a chance to preempt or control the disease. For that matter, as a nation we could prevent tens of thousands of cancers—and 30% of all cancer deaths, according to the NCI—by getting people to stop smoking. This all-too-obvious observation was made by every researcher I interviewed. Alas, this is not a million-dollar commitment. It's a billion-dollar one. But the nation is already investing billions in research, and that doesn't even include the $64 billion a year we spend on treatment. To make the resource shift easier, Congress should move the entire federal war chest for cancer into one bureaucracy, not five. Cancer research should be managed by the NCI, not the VA and Pentagon. Just as important, the cancer leadership, the FDA, and lawmakers need to transform drug testing and approval into a process that delivers information on what's working and what's not to the patients far faster. If the best hope to treat most cancer lies in using combinations of drugs, we're going to have to remove legal constraints and give drug companies incentives to test investigational compounds together in shorter trials. Those should be funded by the NCI—in a process that's distinct from individual drug approval. One bonus for the companies: If joint activity showed marked improvement in survival, the FDA process could be jump-started. "It's going to require a community conversation to facilitate this change," says
This, by the way, is one of those big ideas that the cancer culture didn't take seriously, and would barely fund, for decades. The concept was pioneered 43 years ago by Judah Folkman, now a surgeon at Children's Hospital Boston. While studying artificial blood in a Navy lab, he was struck by a simple and seemingly obvious idea: Every cell needs oxygen to grow, including cancer cells. Since oxygen in the body comes from blood, fast- growing tumors couldn't develop without access to blood vessels. Folkman later figured out that tumors actually recruited new blood vessels by sending out a protein signal. If you could turn off that growth signal, he reasoned, you could starve the tumors and keep them tiny. The surgeon submitted a paper on his experiments to various medical journals, but the article was rejected time and again. That is, until an editor at the New England Journal of Medicine heard Folkman give a lecture and offered to publish it in the Journal's Beth Israel Hospital Seminars in 1971—ironically, the year the War on Cancer began. After decades of resistance, the cancer culture has finally come around to Folkman's thinking—as the reception greeting Avastin makes clear. Still, the biggest promise of anti-angiogenesis drugs will be realized only when doctors can use them to treat earlier- stage patients. That's because the drugs designed to choke the tumor's blood supply often take a far longer time to work than traditional toxic chemo—time that people with advanced disease and fast-growing cancers may not have. Doctors also need the freedom to administer such drugs in combination. Tumors recruit blood vessels through several signaling mechanisms, researchers believe, so the best approach is to apply several drugs, cutting off all routes. Who knows? A new paradigm in treatment may emerge from Folkman's 40-year-old idea. Yet to make this simple and seemingly obvious shift, the entire cancer culture must change—from the rules governing drug approval to tort law and intellectual property rights. Science now has the knowledge and the tools; we need to act.