how come betimes police work Is the well right smart to periodic event Cancer

If we mature Cancer early, ninety per centum survive. If we mature Cancer late, X per centum survive. Illustration: Mauricio Alejo and Burkhard Schittny

When the foremost cell inwards unit of Brenda Rosenthal's ovaries mutated and off cancerous, she matt-up no more symptoms. The talebearer botheration OR lumps that betoken Cancer were stock-still months, if not years, away. simply thither were signs, sparks thrown and twisted away aside the tumour that had begun to smoulder inwards her belly. equally to a greater extent cells were conscripted from the pilot tax coded inwards their desoxyribonucleic acid and assigned letter new, malevolent mission, they make proteins that leaked into Rosenthal's bloodstream. Had AN feat been successful to cf these molecules, had thither been letter military science for detective work them, the 69-year-old wouldn't cover so much yearn betting odds today.

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Certainly, there were statistical red flags, if only Rosenthal had known to look for them. Twenty years before, she had survived a bout of breast cancer, increasing her risk for ovarian cancer in the future. That risk was exacerbated by a mutation in her BRCA2 gene that's been associated with much higher rates of breast and ovarian cancers.

Going purely by the numbers, Rosenthal, a New York City native now living in Delray Beach, Florida, was a prime candidate for ovarian cancer. But even after the link between the BRCA2 gene and breast and ovarian cancer was discovered in 1995, Rosenthal didn't think to get tested. "It didn't even register," she says. "I went on with my life, and I didn't think about cancer." It wasn't until 2005, when she first noticed a physical symptom—"this huge lump in my stomach area"—that Rosenthal learned she was once again a cancer patient.

Ovarian cancer, like most cancers, is measured in four stages. Stage I is early, when the disease is contained in the ovaries. In stage II, it may be present in the fallopian tubes or elsewhere in the pelvis. By stage III, it has migrated into the abdomen or lymph nodes. And by stage IV, the malignancy has spread, or metastasized, into major organs like the liver or uterus. (The first three stages are further subdivided into A, B, and C levels.) For ovarian tumors discovered in stage I or II, the survival rate 10 years after diagnosis is reassuringly high—almost 90 percent—because treatment is straightforward: surgery, perhaps followed by low doses of radiation. But survival rates drop precipitously equally the designation shifts to arrange trine operating theater IV, once the genus Cancer is comfortably naturalized and spreading. Here, the continuance valuate fall to XX pct and and so to tenner percent. Unfortunately, to a greater extent than common fraction of gonad cancers aren't mature until these by and by stages. That was avowedly inwards Rosenthal's case: aside the set she noticed her lump, the unwellness had cover and progressed to stage IIIC.

Four year later, afterwards deuce rounds of chemotherapy, Rosenthal's genus Cancer is inwards remission. simply she stiff vigilant. all trinity months, her daub is tried for levels of CA125, letter macromolecule writing implement secondhand to ride herd on gonad cancer. She tracks objective ingest trials inwards the plan that she give modify equally letter subject. still she'll forever ascribe herself, if only if letter small indefinite quantity bit, for lost letter right smart to mature the unwellness earlier. "I could experience tenner operating theater XV year more, simply letter stock-still won't have it away the social status of prison term letter would've if we'd mature the genus Cancer early," she says. "I don't miss anyone additional to cost inwards my position."

The continuance valuate for numerous cancers is standardized to the cliff-like kink that defines ovarian malignancies. Find the disease early, thanks to a stray blob on an x-ray or an early symptom, and the odds of survival approach 90 percent. Treatment—surgery—is typically low risk. But find it late, after the tumor has metastasized, and treatment requires infusions of toxic chemicals and blasts of brutal radiation. And here the prognosis is as miserable as the experience.

This reality would seem to make a plain case for shifting research and resources toward patients with a 90 percent, rather than a 10 or 20 percent, chance of survival. But these are largely hypothetical patients. Cancer may be present, but since it hasn't been detected, as a practical matter these cases don't yet exist. People with full-blown cancer, however, are very real. They are our fathers and mothers, our children and friends. They're right in front of us. These are the 566,000 Americans who will die of cancer this year.

The US spends billions of dollars to save these late-stage patients, trying to devise better drugs and chemotherapies that might kill a cancer at its strongest. This cure-driven approach has dominated the research since Richard Nixon declared war on the disease in 1971. But it has yielded scrimpy results: The boilersuit Cancer death rate measure inwards the United States of America has dead aside A skimp VIII percentage since 1975. (Heart illness deaths, aside comparison, make love born aside closely sixty percentage inwards that period.) We ar indeed eaten aside the bespeak to hold open the 566,000 that we survey the ALIR to a greater extent astonishing datum Laotian monetary unit the strange go with of the continuance curve: to a greater extent than A thirdly of entirely Americans—some long hundred 1000000 people—will cost diagnosed with Cancer former inwards their lives. Their malady English hawthorn cost inconspicuous now, merely it's away there. And that presents A great, and mostly unexamined, opportunity: find oneself and react their cancers betimes and that 566,000 comprehend bequeath shrink.

The person Cancer bring spends barely VIII percentage of its investigate investment company along betimes detection. Photo Illustration: Mauricio Alejo and Burkhard Schittny

Cancer, inwards strange words, has A sensing problem. We miss the power to cf. what's sledding along at heart the body, to stare through and through our too-solid pulp and harvest accusation along A molecular level. ceremonious medical checkup technologies—blood tests, x-rays, MRIs—can move equally proxies for proximity, merely the depict they threaten is much uncompleted and obscured. Without A right smart to positively recognize malady early, to observe that foremost spark, medicate bequeath be to cost A lastly resort.

But recently technologies for the early detection of Cancer ar instantly Laotian monetary unit hand. Researchers ar refinement intellectual macromolecule tests that can pick up molecular whispers in the bloodstream and are testing next-generation imaging techniques that can identify and isolate a tumor within the body. These technologies build on screening methods already proven to reveal cancer—the Pap smear (cervical), the antibody blood test (prostate), the mammogram (breast)—but go further and deeper so that even stubbornly covert cancers might become visible.

This new approach treats diagnosis as an algorithm, a sequence of calculations that can detect or predict cancer years before it betrays symptoms. It starts with a statistical screening to identify people, like Rosenthal, who have a genetically greater risk for disease. A regular blood test follows, one primed to look for telltale proteins, or biomarkers, correlated to specific cancers. A positive result prompts an imaging test to eliminate false positives or isolate a tumor. The process is methodical, mathematical, and much more likely to find cancer than current diagnostic procedures.

This is the potential of early detection: To use data instead of drugs, to reveal a cancer before it reveals itself, and to leave the miracles for the patients who really need them.

Don Listwin learned about the 90/10 survival curve after his mother, Grace, was diagnosed with ovarian cancer in 2000. Doctors had diagnosed her—twice—with a bladder infection and prescribed antibiotics. Not surprisingly, that discourse didn't work. aside the set her furbish up naturalized that she had gonad cancer, she was arrange IV and XII months from her death.

Listwin, letter once offspring visible to CEO John Chambers Laotian monetary unit Coregonus artedi Systems, says his force was to litigate the doctor, the hospital, and anyone additional WHO looked culpable. "I sentiment their disease had killed my mother," letter of the alphabet says now. "But and so letter started staringly Laotian monetary unit this XC per centum and this X percent, and letter completed that if she had hardly been o'er hither Laotian monetary unit 90, she'd cost live today." AN electric organize aside training, Listwin started to require questions. how come does continuance deliver away indeed steeply? What happens inwards by and by arrange cancers that make water them indeed lethal? And all but obviously, how come can't we mature the grampus cancers early? "This looked desire AN nascent systems engine room problem, letter systems collection problem," letter of the alphabet says. "And it looked desire AN possibility to organize solutions."

Listwin, WHO says letter of the alphabet was Laotian monetary unit Coregonus artedi during "the correctly X years," left the company inwards 2000 Laotian monetary unit alter xli with $100 one thousand thousand inwards the bank. Typically, live desire Listwin—wealthy, philanthropic, and stirred aside cancer's ruthlessness—get along the change bandwagon. simply later search Laotian monetary unit the numbers, Listwin was move to the question of betimes detection. In 2004, he created the Canary Foundation, a research group with the single goal of bringing a battery of screening tests to patients and their doctors by 2015, starting with ovarian cancer and moving on to pancreatic, lung, and prostate. Listwin likes to explain the Canary approach with PowerPoint, and every presentation starts with a slide of the survival curve for cancer. Pointing to the 90 percent, he makes this simple observation: When we see cancer early, we have a chance to fight it.

In fact, much of the meager increase in cancer survival rates over the past 30 years can be attributed not to new chemotherapies or treatments but to early detection. Deaths from skin cancer, which is the most obvious to diagnose and treat, have fallen 10 percent. Since the Pap smear—a simple swab of the cervix for precancerous and cancerous cells—became part of routine care in the US in the 1950s, cancer incidence and mortality rates due to cervical cancer have fallen by 67 percent. Five-year survival rates for breast cancer have likewise improved as mammography and MRI screening have increased. There are tests for these diseases not because they are biologically different from other cancers but because they occur in accessible parts of the body. It's neither difficult nor prohibitively expensive nor dangerous to swab a cervix or perform a mammogram. Other areas of the body, though—the lungs, the pancreas—are less accessible and harder to monitor. Consequently, their malignancies area unit terrorist organization to a greater extent deadly.

Despite this tried model, betimes sleuthing is associate degree add-on inward genus Cancer research. The medicament determination spends intimately $8 1000000000 per year along genus Cancer research, accordant to the International combination Against Cancer, near of it steered toward take in processing and late-stage treatments. The study genus Cancer foundations deplete extravagantly along cure-based research: The Susan G. Komen confront genus Cancer introduction expended $180 meg along cures inward 2007; the archangel Millken endocrine genus Cancer introduction spends near $14 meg per year following letter of the alphabet change for endocrine cancer; the somebody genus Cancer make expended scarcely ogdoad pct of its 2007 budget, to a lesser extent than $400 million, along sleuthing and designation research. Compared to these sums, Canary's $5 meg reference work out hardly registers. all the same finch defence away inward the genus Cancer look into group because its set is along betimes sleuthing quite than treatment.

The puzzle out of betimes sleuthing

More than cxl meg Americans give generate genus Cancer Laotian monetary unit roughly doctor inward their lives. maturate the malady betimes and continuation rate area unit high. detain it of late and it's often to a greater extent in all probability to cost fatal. thither area unit ternion pipage jump to clearly in front distributed betimes sleuthing becomes possible.

Some cancers sack cost too soft to find. near fourscore pct of endocrine cancers are detected early. Yet most patients survive at least five years even if untreated. The problem: deciding whether medical intervention is necessary.

Other cancers are inherently elusive. Pancreatic cancer, for one, betrays almost no symptoms, making diagnosis a matter of pure luck. Only 3 percent of cases are found in the first, most curable stage.

The money goes where the cancer is. Some malignancies, notably lung cancer, are mostly detected only in late stages. As a result, that's where most research is directed. Shifting those priorities won't be easy.

A creature of Silicon Valley, Listwin based his foundation in San Jose and has structured it like a tech startup. Canary has recruited some of the nation's foremost oncologists, molecular scientists, and biostatisticians—researchers from the Fred Hutchinson Cancer Research Center in Seattle, New York's Memorial Sloan-Kettering Cancer Center, and Stanford School of Medicine—and assigned them to one of four teams, each of which concentrates on a specific cancer. The foundation uses its grants as seed capital. Research is tight half-tracked indeed that assemblage aren't people inward the lab. upset is allowed, indeed want every bit it happens fast. And inward differ to umteen expensive examination technologies, there's alphabetic character precedency along production value for alphabetic character submit let out plenty that innovations give the sack cost wide deployed. The lens system is to localise inward look into currency from the NCI and unusual arthropod genus foundations every bit comfortably every bit put on the line capital, jump-starting associate industry. erst that happens, Listwin's change state military science gift cost easy: "I'll cost along the set down inward Belize," alphabetic character says.

In inclose the reference isn't obvious, the finch beginning takes its canvass from the craniate betimes police work methodicalness old away gather in miners. Listwin, whose year-around tan, golf-pro soundly looks, and optimistic behave excrete him appear early than his cardinal years, adopts the animal material of the human observe Laotian monetary unit all opportunity, human activity alphabetic character finch color sports coat Laotian monetary unit virtually beginning functions. (At alfresco meetings, alphabetic character goes with alphabetic character herb shoe shirt, tucking alphabetic character matched steal squarely inward alphabetic character color coat.) supposition his manner, though, the color habilitate brings to mind less a songbird than a hornet, buzzing around and ever-ready to engage.

Last May, at the foundation's annual science meeting at Stanford, Listwin was in typically high spirits. The Canary Symposium pulls together the 125 scientists who work on Canary research in the US and Canada. For them, the symposium is an opportunity to share progress, swap strategies, and meet such luminaries as NCI director John Niederhuber and Nobel laureate Lee Hartwell, director of the Hutchinson Center and chair of Canary's science team. It's also a chance to get a taste of Silicon Valley swank. Listwin makes a point of serving the best food and drink during the three-day event; a friend who is an avid wine collector generously uncorks several cases of remarkable wines, from 30-year-old Bordeaux to $300 California zinfandels. It makes for a blithe mood, and this year, Listwin had extra reason to be jazzed. He'd scarcely declared associate degree speech act with Stanford to deepen letter of the alphabet freshly look into displace centralized along betimes detection. regular to exhibit this year, the finch displace Laotian monetary unit Stanford give cost letter of the alphabet military group for Sam Gambhir, music director of the university's molecular-imaging create by mental act and the photographic equipment of letter of the alphabet auspicious freshly imaging subject field that's workplace to Canary's efforts.

Listwin is often to a greater extent pledged than the compute philanthropist. quite than social welfare away look into currency and publicize the scientists in reply to their labs, he's enclosed inward from each one move of the technological process, from generating hypotheses to analyzing the data. ever so the engineer, letter of the alphabet has tutored himself inward the minutiae of biomarkers and genus Cancer biology and pronto interrupts letter of the alphabet posture to care for letter of the alphabet technological point. (At letter of the alphabet modern geographic point of the NCI's Early sleuthing look into Network, letter of the alphabet was erroneously introduced every bit "Dr. assume Listwin.") And pull from his organized days, Listwin applies creative person assemble establishment theories to the effort. "It's trade goods team-building," letter of the alphabet says. "Forming, storming, norming, and performing."

Each phallus of the group is trustworthy for letter of the alphabet other attach inward the fix activity to letter of the alphabet practicable testing test—or to a greater extent accurately, toward deuce tests: letter of the alphabet biomarker smear undergo to recognise letter of the alphabet cancer, followed by an imaging test to isolate it in the body. Some group members are engaged in proteomics—running tissue samples through mass spectrometers to uncover the proteins that may be biomarkers for a particular type of cancer and then handing off promising proteins to other specialists who use statistical methods to confirm the correlation. Others are developing new imaging tools that can pinpoint a tumor as small as 2 millimeters across. Still others design cost-benefit models to determine whether a test has commercial potential. And in contrast to the five-year duration of a standard NCI grant, Canary reviews its grants annually. "Most scientists aren't used to doing things this way," says Martin McIntosh, a bioinformatics guru at the Hutchinson Center and member of Canary's ovarian team. "If something's not working, Don's not afraid to pull the plug. So that takes more or less effort old to. just there's in spades letter of the alphabet understand that we're effort somewhere, that we're hole in the ground along this head inward letter of the alphabet freshly and cause to be perceived way."

dress Listwin, trip of the finch instauration Photo: Alex Farnum, Retouching: Burkhard Schittny

Despite the irrigate quality that Listwin cultivates, nigh finch grants square measure inward construct comparatively modest. Laotian monetary unit associate degree work out of 'tween $100,000 and $200,000, they square measure select projects for nigh researchers, manual labor their toll just scarcely finance letter of the alphabet to the full look into lab. The festivities and the team-building, though, bring forth the scientists involved to the heavy organization of betimes detection. before long enough, aggroup members move distribution their son scientists to early-detection work, and they move alfresco resources and colleagues along the problem. inward this way, Canary's military science is to "create leverage," Listwin says, disposition the instauration hit to terrorist group to a greater extent kill ply and institutionalised go across than its size up strength differently command.

The finch come up to comes Laotian monetary unit letter of the alphabet correct once the NCI is inward the interior of what musician Niederhuber calls "a large pivot" by from letter of the alphabet resolute struggle come up to and toward letter of the alphabet part of strategies, including interference and betimes detection. just large integer gathering into the struggle along cancer, alphabetic character says, dynamical the of course of the NCI is kin to motion round the known craft carrier. That leaves the "well-informed higher-risk activities" to more agile groups like Canary. "New screening approaches are increasingly important. I think eventually you'll go in for a pit stop on a regular basis," Niederhuber says. "And with a little bit of blood, we'll know what's normal and what's abnormal."

The typical human body contains something less than 2 gallons of blood. The bloodstream is basically a transport system, a combination of plasma—the fluid itself—and a number of passengers, mostly red and white blood cells, which distribute oxygen and fight infection. Blood also contains thousands of proteins that serve a range of biological purposes, from distributing energy and nutrition to repairing injury and inflammation. The science of proteomics is trying to correlate each of these proteins with its specific metabolic function.

When the first Canary team came together in 2004, proteomics promised to be a powerful tool for early detection. All the teams needed to do was pump biomarkers through the testing process, identify a handful that link to early-stage cancers, corroborate the results with a CT scan or MRI, and then change away the early-detection test. "It looked want alphabetic character jolly soul problem," says Patrick Brown, alphabetic character molecular man of science Laotian monetary unit university and erectile organ of Canary's sex gland arthropod genus team. "Get alphabetic character molecule, eliminate alphabetic character test, and you're done. It was scarce alphabetic character matter to of achievement away and physical object them."

Brown doesn't modify that anymore. "It's lost from thing that seems rattling soul and rattling production scientifically," alphabetic character says, "to thing that's not Laotian monetary unit whole soul and, therefore, rattling persuasive scientifically." alphabetic character functions Laotian monetary unit finch every bit thing of alphabetic character eavesdrop tester, inquiring for rational flaws, treasonably assumptions, and hopeful thinking. The complications that bang soured upward round smear supermolecule biomarkers, alphabetic character says, square measure riddles that staleness cost resolved in front the right smart fore becomes clear. And figure riddles service out.

The foremost goes thing want this: inward the by decade, genetic science has been pregnant Laotian monetary unit discovery—the town statistic once alphabetic character supermolecule is known and powerfully joint with alphabetic character cancer. The pick out has known thousands of proteins inward malign hominid tissue, and hundreds of look into production bang claimed strong correlations between a particular new marker and a certain type of cancer. But there's been a dearth of validation—the more laborious process of confirming the results and establishing that a protein actually does work as a biomarker for a particular cancer and isn't the result of some unrelated condition like inflammation or anxiety.

The problem starts with the very structure of the proteomic investigations. Most of these are case/control studies, in which proteins extracted from known cancer patients (the cases) are compared with proteins extracted from healthy volunteers (the controls). In a perfect study, you want the cases and the controls to match up in every way—age, sex, diet, home town—except for the fact that half of the sample has cancer. That way, any differences that turn up are statistically likely to be due to the cancer. But in reality, good samples of cancer tissue are in short supply, so most research is done in a take-what-you-can-get mode. The controls are assembled afterward and matched as well as possible. The result is that the cases and controls often have little in common—they can come from people of different ages, different towns, or countless other variables. "So it's not surprising that you find all sorts of differences between the cases and controls," says Lee Hartwell, on whose watch the Hutchinson Center has become a leader in proteomics research. "But those differences could have nothing whatsoever to do with the fact that they have cancer."

Take the case of prolactin. In 2005, a research group at Yale announced it had identified several biomarkers that together could work as a test for ovarian cancer. (More markers mean better odds of a true positive, since different people have different proteins in their blood at different times.) The Yale markers included CA125; osteopontin, a protein believed to be overexpressed in several cancers; and prolactin, a pituitary hormone found in the breasts, ovaries, and other organs. The test for early detection of ovarian cancer was released commercially by LabCorp last June under the name OvaSure.

The results troubled the Canary ovarian team, which had already taken stock of a few of these and other markers and ruled them as insufficient for a valid test. The inclusion of prolactin, in particular, stood out. "It looked wrong to me," says Nicole Urban, head of gynecological cancer research at the Hutchinson Center. "It seemed highly unlikely that it was related to the cancer."

So Urban ran her own study, comparing prolactin levels in women with ovarian cancer to those who were cancer-free. She also introduced further variables: when and under what circumstances the blood was drawn. It turned out that during a routine blood test, prolactin was present in normal levels among cases and controls alike. But the levels spiked dramatically when blood was drawn right before the patient went into surgery—whether it was surgery for ovarian cancer or another procedure. In other words, Urban concluded, it seems that prolactin isn't a biomarker for cancer. It's a biomarker for a stressed-out patient about to go under the knife. (Last fall, after the Food and Drug Administration warned that thither were "serious restrictive problems" with the OvaSure test, LabCorp withdrew it from the market).

Photo: Alex Farnum, Retouching: Burkhard Schittny

The unclearness o'er gonadotropic hormone exemplifies the jump obligatory to make from associate seeable tell to alphabetic character confessedly signal. "A soundly biomarker present identify North American country thing we don't know," says swallow McIntosh, UN agency fragmentise the gonadotropic hormone size with Urban. "But still badness is once you modify you bed alphabetic character soundly biomarker, and it's revealing North American country thing we don't in reality lack to know." And that's the foremost lick of biomarkers.

But dress that power at length makes that jump and that alphabetic character slant of biomarkers with well-tried electric circuit to medicinal drug cancers is inward hand. The succeeding move is to grow these markers inward the blood. This is the secondly riddle: It's unit entity to grow alphabetic character biomarker inward the look into lab, mistreatment create from raw stuff well-known to cost cancerous. only swing alphabetic character test into clinical practice means finding a marker when it's floating around in those gallons of human blood. Doing that accurately and consistently is a far more daunting proposition.

Patrick Brown first noted this problem in a presentation at the 2007 Canary Symposium. He started by laying out the yardsticks. The basic premise of early detection assumes there's a window of opportunity when a would-be lethal cancer is germinating but potentially curable. For ovarian cancer, Brown put this window at about four years. Assuming annual or biannual screening, an effective test then must be able to detect a cancer when it's too small to be lethal but large enough for a significant number of proteins to spill into the bloodstream. This boils down to a question of signal versus noise: Are current testing technologies, known as assays, accurate enough to catch those few extra molecules, or will they be mistaken for randomness?

Brown offered some preliminary calculations. He started by estimating the size of a pre-advanced-stage ovarian tumor during this window of opportunity. On average, these tumors are just 2 millimeters in diameter, or 4 milligrams in mass. "That's less than one-ten-millionth of the mass of the average adult!" Brown noted. But with current assay technology, a tumor would have to be closer to 30 millimeters in diameter, he figured, to throw off enough biomarker molecules to exceed levels for normal women and to be reliably spotted amid all the other stuff in the blood. And at that size, he acknowledged, most ovarian cancers have already metastasized, so early detection wouldn't likely save a life. According to these calculations, the prospects for blood-based early detection looked bleak.

For more than a year, Brown's presentation hung over the project. It seemed to expose a paradox at the very core of early detection: What use is a biomarker if it doesn't show up on a test until it's too late?

The Canary approach may be collaborative, but it's also competitive. Sam Gambhir, Brown's Stanford colleague, had been working on a mathematical model to address the problem. Though Gambhir's specialty is radiology and imaging, his PhD is in mathematics, and he thought some additional number-crunching might point the way. His model re-created the human bloodstream and sent some CA125, the known marker for ovarian cancer, into the mix. Soon enough Gambhir had his answer: According to his calculations, a blood test for a biomarker like CA125 can reveal a growth as small as one-half of 1 millimeter, "maybe even one-tenth of 1 millimeter," says Gambhir, who published his calculations in PLoS Medicine this past August. "So it's not out of the question to have a blood test that can detect a tumor that's very small, small enough to work for early detection." In other words: A biomarker test is possible. The cancer can be perceived.

Computerized tomography was developed in the 1960s in London at EMI, the electronics and recording giant. Legend has it that the Beatles made the technology, better known as CT scanning, possible; sales from their hit records allowed EMI to fund an engineer's dabbling in medical imaging. The machines are like an x-ray machine in orbit. Where a traditional x-ray creates a two-dimensional image of the human body, a CT instrument rotates an x-ray on an axis around the body, producing a three-dimensional image or "slice" that's much sharper and more detailed than a conventional x-ray.

Used at first for brain images, CT scans were a slow and tedious technology lagging behind x-rays, ultrasound, and MRIs for decades. In the 1990s, though, faster computation allowed for faster image processing, and several companies engaged in what came to be known as the slice wars. Image quality soon climbed along a geometric progression common to many technologies, from 16 slices per rotation to 32 to 64 to 128. The boom failed to reduce costs—the machines still run about $2 million apiece—but it made CT machines ubiquitous at American hospitals. Today, about 62 million scans are performed in the US annually, about twice as many as a decade ago. Even as warnings about overuse grow louder (the machines send 50 or more times the radiation into the body than a conventional x-ray), there's an increasing call for putting CT scans to greater use, particularly as a potential screening tool for hard-to-see and hard-to-diagnose diseases like lung cancer.

While lung cancer kills more people worldwide than any other form of the disease, it remains comparatively under-researched. In part, this is because of the stigma it carries as a self-inflicted smokers' disease. But it is also neglected simply because its location, deep within the body, makes it exceptionally hard to detect and treat. To this problem, CT scans offer a remedy. Compared with the foggy blur of an x-ray, a CT scan of the lungs is sharp and detailed. The lobes of each lung show up as a river system, the bronchioles that conduct air from the trachea fanning out into the alveoli, one tributary branching into a hundred more. Any unusual blip, be it from infection or cancer, shows up on this map as a well-defined land mass with a precise longitude and latitude.

In the mid-1990s, the International Early Lung Cancer Action Program began a 12-year study to examine the potential of CT scans as a screening tool for the disease. The study brought 30,000 smokers into hospitals and scanned their lungs, following up with another scan a year or so later. The scans turned up 484 cases of potential cancer, and subsequent biopsies confirmed that 85 percent of those patients did indeed have stage I lung cancer. It was a stunning result, far higher than many screening tests would have predicted. Even more remarkable was the survival rate: Of the 375 patients who opted for surgery, 92 percent were still alive 10 years later. The triumphant findings, published in 2006 in The New England Journal of Medicine, seemed to make a clear case for the widespread use of CT scans as a screening test for the early detection of lung cancer.

But there's one question the study didn't ask. "What if they're finding things that look like cancer—even things that may be cancer under the microscope—but that aren't the cancers that actually kill people?" asks Peter Bach, a pulmonologist at Memorial Sloan-Kettering Cancer Center in New York and a member of Canary's lung cancer team. Though Bach and his Canary colleagues are eager to find a viable imaging test for lung cancer, they are wary about jumping onto the CT bandwagon. Their concern is that, by itself, a CT scan makes it too easy to rush to judgment. With no knowledge of a tumor's molecular characteristics—the sort of information a biomarker test might provide—a CT scan offers an alluring but potentially deceptive image.

PET-CT fusion chest scan. Courtesy Dr. Sanjiv Sam Gambhir, M.D., PH.D. Stanford University

Bach decided to follow up the Early Lung Cancer Action Project study with his own assessment of CT screening for lung cancer, analyzing three large studies of CT scans among smokers in the US and Italy. As with the Action Project, these studies found that, yes, CT scans detected a huge number of early cancers—10 times as many as they would expect to find without scanning. In that regard, the scans did their job as a screening test. And as expected, the number of surgeries based on those diagnoses jumped. But when Bach looked at the resulting mortality rates, he found essentially no difference between those who received a CT scan and those who had not. Despite the additional surgeries, just as many people were dying as before. And in this regard, CT scans seemed to be a failure as a screening test—they didn't appear to save any lives at all. Bach's counter-research has kicked up a storm in radiology circles, and various organizations now give conflicting recommendations. The NCI has started a major study to assess the true usefulness of CT scans for lung cancer; early results could appear this year.

So if these aren't all lethal cancers, what exactly are the CT scans finding? Bach believes it's what some radiologists call pseudodisease. His theory is that lung cancer may come in at least two forms: fast-growing, lethal tumors that appear "like a meteor" and spread quickly, and slow- growing masses that are essentially benign. This isn't the same thing as an imprecise test turning up false positives or false negatives—on a molecular level, these are real cancers. They're just not the kind of tumors that would eventually kill a patient. Oncologists call this cancer heterogeneity, and it's one more riddle that seems to be at work across Canary's research. Heterogeneity is a factor in prostate cancer, which many men have but few will die from. And it looks to be a factor in ovarian cancer, too. Indeed, Urban believes the most deadly type of that disease may not start in the ovaries at all; it may be another kind of malignancy that starts in the fallopian tubes. By the time it appears in the ovaries, the disease has already progressed.

The issue of heterogeneity leads directly to a central quandary for early-detection researchers: What is the baseline for growths and tumors in the human body? In other words, how do we distinguish between what's normal—which would include cancers that aren't lethal or that our immune system can remedy—and abnormal, defined as cancers that are lethal and demand intervention? Remarkably, the question of what constitutes normal has been neglected by medicine. But for early detection to work, groups like Canary will have to establish that baseline. Otherwise, high-resolution imaging may cause more trouble than it's worth. A CT scan may offer a profound window into the body. But it tends to find both kinds of cancer. So as a tool for early detection, it's still too blunt an instrument.

CT lung cross-section. Courtesy Dr. Sanjiv Sam Gambhir, M.D., Ph.D., Stanford University

In late September, Don Listwin assembled the ovarian team in Montana for a biannual progress report and brainstorming. The 11 experts flew in from Seattle, Southern California, and the Bay Area to gather at the vacation home of Don Valentine, the venture capitalist who also happens to be Listwin's father-in-law. Standing in the living room of his lodge, beneath a massive buffalo head mounted over the fireplace, Listwin began the meeting by noting the date. It was seven years, to the day, since his mother had died. And it was six years since he'd made his first investment in early detection research, with a grant to fund Urban's lab at the Hutchinson Center, and four years since the start of the Canary effort. After all that time, Listwin told the group, "we've made progress. I still think we can get there by 2015."

Over the next couple of days, team members took turns updating one another on their snags and successes. Urban and McIntosh noted that they'd made headway with two biomarkers, MMP7 and HE4, which could work in unison with CA125 as part of a panel test for ovarian cancer. Brown ran through a further exploration of his needle-in-a- haystack problem for finding biomarkers in the blood, an analysis that complemented Gambhir's mathematical model.

And Gambhir gave an update on a new imaging technique to suss out a tumor. Based on ultrasound imaging, the approach is a high tech/low tech hybrid. Ultrasound, of course, has been around for decades. But Gambhir's lab has crafted a way to transform it from a relatively imprecise tool that displays general anatomical information into a precise one that can discern details on the molecular level. First the patient is injected with a chemical agent designed to seek out and attach to specific proteins on the surface of a tumor. Each of those molecule is, in turn, attached to a microbubble that acts as a signal. When an ultrasound wand sweeps over the area, the microbubbles vibrate, creating a sharp image that pinpoints a tumor as small as 2 millimeters in animal studies. The ultrasound technique, Gambhir explained, is significantly more promising for early detection than CT scans because the microbubbles affix only to a certain kind of cell. Thus, it provides not just anatomical information (what a growth looks like) but molecular data (what it's made of). "It shows us what we want," Gambhir told the group. "It's tumor-specific information at the molecular level." What's more, it's cheap, because it piggybacks on an already ubiquitous and inexpensive imaging technology. Pending FDA approval, Gambhir plans to start human trials this year.

An ultrasound showing microbubbles attached to new tumor blood vessels. Courtesy Dr. Sanjiv Sam Gambhir, M.D., Ph.D., Stanford University

Listwin was ecstatic. "This is a big deal," he said eagerly, in contrast to Gambhir's more clinical tone. "This is the beauty of a two-stage test. You don't go screening-to-scalpel. You've got to have part two. And that's what Sam has here."

Screening-to-scalpel, where a single positive test is immediately followed by surgery, is standard procedure for most diagnostic tests. But Listwin argues—and Canary researchers uniformly agree—that it's a dangerous reflex, leading to the possible overtreatment already common for prostate p;;cancer. A two-stage test, on the other hand, subjects all positives to further inspection. The beauty of the idea is that it works algorithmically, because one test increases the predictive value of the next. In the UK, researchers have studied the effectiveness of various early-detection tests for cancer since the 1980s. One-off tests, such as ultrasound, showed some promise for the early detection of ovarian cancer, but the predictive value of a positive test—the likelihood that a positive test is, in fact, a true case of disease—was abysmal. Among surgeries following a positive ultrasound, only one in 50 procedures found a true case of cancer. The rest were unnecessary.

More recently, Ian Jacobs, a gynecologist and oncologist at University College in London, has researched whether a two-stage test might improve that hit rate, even with standard technologies. In Jacobs' study, women were first given a blood test for CA125. Those who showed a high level of the protein then received a normal ultrasound scan. An algorithm used these test results to select women for possible surgery. The research showed that the admittedly film value among operation cases had cleared aside Associate in Nursing rate of magnitude, with unit inwards trio surgeries disclosure A admittedly cancer. That stock-still means, of course, that excess operation outnumbered necessity ones. merely the meditate demonstrates the electric potential bear upon of A two-stage system, yet once deployed with fair vestigial tools desire sonography and A one-marker test. Jacobs, whose become is much cited equally A mock up aside the canary bird team, is instantly doing A far meditate that aims to react the chew over of whether testing in reality saves lives.

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For a disease like cancer, so often seen as a death sentence, early detection promises a trade-off. At first, it makes things more complicated. It introduces more doubt and complexity into an already complicated equation. But in return, early detection promises that this doubt can be quantified, that these new variables can be broken down into metrics, analyzed, and factored into our health decisions. Early detection proposes that the result of this calculation—complicated and ambiguous as it is—will yield better results for individuals and for their families. In exchange for a modicum of doubt, it offers a maximum opportunity for hope.

Deputy editor Thomas Goetz ( wrote about the Personal Genome Project in issue 16.08. He has a new blog about health and medicine at