Posted on Sep 21, 2005, 2 p.m.
By Bill Freeman
When doctors need to peek at mysterious goings-on inside the human body, they can skip the scalpel and rely on MRIs and CT scans. These state-of-the-art imaging technologies, successors to the X ray, reveal exquisitely detailed pictures of various tissues, organs and other anatomy.
Yet some of the most important details are invisible to MRI (magnetic resonance imaging) and CT (computed tomography). They can't reveal the molecular defects that indicate whether an abnormal lump is cancerous or benign. They can't tell doctors which bad genes are active in a patient's tumor or whether a drug is reaching its intended target. The result, says Stanford University imaging researcher Dr. Sanjiv Gambhir: "Everyone is shooting blindly."
But a new generation of far sharper imaging is on the way, deploying the emerging science of nanotechnology and other advanced methods to reveal invisible workings at a molecular and cellular level. Some techniques have just come into use; others are in patient trials (or about to begin them); some of the most daring are still in the lab.
In five to ten years a flurry of new imaging agents--injected into the body to seek out and latch on to defective proteins in tumor cells, brain plaque in Alzheimer's patients, molecular flaws causing rheumatoid arthritis or small blood clots hidden in the brains of people who are about to have a stroke--may emerge. These "molecular beacons," as one researcher calls them, would work with MRIsand CTscans to better pinpoint the presence of disease.
Ultimately these advances may let doctors spot disease-causing abnormalities long before any symptoms surface. Molecular imaging agents could speed the advent of a new era of personalized medicine, in which therapies are tailored to patients' individual gene maps and doctors can monitor the treatments' impacts on a molecular scale.
"We are trying to revolutionize the way we look at the body," says Dr. Ralph Weissleder, who runs a big imaging lab at Massachusetts General Hospital. "A lot of times we are looking at shadows that are hard to interpret," adds Washington University cardiologist Samuel A. Wickline, cofounder of the drug startup Kereos. "In the future we will look at unique molecular beacons" that signal disease.
The science is coming into place, but a big uncertainty remains."It's not clear what the business case is," says Daniel Sullivan, head of the National Cancer Institute's imaging program. Agents can cost half as much to develop as therapeutic drugs, but they may bring in only one-tenth the revenue, $50 million to $100 million annually per agent, Sullivan says. Most big drugmakers have ignored the area, leaving the field to midsize firms such as Germany's Schering and boutiques like Advanced Magnetics.
Still the dramatic promise of molecular imaging has attracted a raft of startups and big guns such as General Electric and Siemens. "We want to be able to see the molecular signature of disease," says molecular biologist Michael Montalto, who sleuths for new brain-imaging agents at a GE lab in Niskayuna, N.Y.
GE spent $9.4 billion last year to acquire the British molecular diagnostics firm Amersham and its line of imaging agents used for CT and MRI scans. In May Siemens of Germany paid $1 billion for CTI Molecular Imaging in Knoxville, Tenn., a leader in PET (or positron emission tomography) scans, which detect cellular metabolism.
PET scans, invented in the 1970s, long were the neglected sibling of MRI and CTscans. But in the past five years their use has exploded, and the earliest examples of new molecular agents are showing up here. While MRI and CT capture images of anatomy, PET measures body chemistry. It involves injecting tiny amounts of a radioactive sugar called FDG into patients to spot areas of rapid metabolism. Fast-growing tumors gobble up the glucose more quickly and show up as hot spots on the resulting scan.
PET technology was confined to the lab for many years but took off after Medicare started covering the scans for cancer patients in 2000. More than a million PET scans were done last year, and their number is growing upwards of 30% annually. In 2003 a study showed PET's strengths. Assessing a tumor's spread in lung cancer patients by using PET and CT combined was far more accurate than using either technique alone, researchers reported in the New England Journal of Medicine. PET finds the hot spots, and CT maps their anatomical location.
Now scientists are working on new radioactive tracers that bind to different types of cellular structures. One tracer, FLT, being tested by the National Cancer Institute and GE detects the DNA synthesis that occurs when a cell divides. FLT may help oncologists get an immediate readout on whether cancer drugs are working, instead of having to wait a month or more for tumor shrinkage to show up on a CT scan. (GE produces equipment that hospitals use to synthesize the substance.)
One promising PET pursuit involves tracers that can monitor the buildup of toxic amyloid protein fragments in the brains of Alzheimer's patients. They are a hallmark of the disease and may cause brain-cell death. But until now the only way to verify their presence has been postmortem, during an autopsy, and this has held back research for a cure.
Both GE and Siemens are testing PET agents that can detect plaque buildup while patients still are alive--and perhaps even before they develop symptoms. GE's agent, licensed from the University of Pittsburgh, is a radioactive version of one of the chemical dyes used by pathologists to spot amyloid during autopsies. It was devised by the school's William Klunk, a geriatric psychiatrist, and radiochemist Chester Mathis. Klunk says one day a brain-plaque screening could do for Alzheimer's disease what tests of blood pressure and cholesterol levels did for heart disease.
The Pittsburgh compound, injected into the body, filters into the brain, gloms on to amyloid protein present in the cortex and sends out a radioactive signal that can be detected by a PET scanner. In a study of 25 patients, researchers were able to clearly distinguish plaque levels in 16 with mild Alzheimer's versus 9 healthy controls, they wrote in a study in Annals of Neurology in 2004.
Siemens is testing a plaque detector from UCLA called FDDNP; it homes in on both plaques and another Alzheimer's pathology called neurofibrillary tangles. In tests of the agent on patients with mild cognitive impairment, PET scans have shown how amyloid deposits slowly spread as the disease progresses to full-blown Alzheimer's, says Jorge R. Barrio, a molecular pharmacologist at UCLA.
Initially the Alzheimer's PET tests will help drug firms get an early readout on whether their experimental antiplaque drugs are working. Roche and Eli Lilly have such compounds in early tests, and they recently hooked up with GE. One day people at high risk for the disease, instead of waiting for signs of dementia to emerge, could be screened at age 65 or 70 for traces of amyloid buildup in the brain and start taking antiamyloid drugs to stave off dementia, says researcher Klunk.
Many doctors would like to be able to detect molecular abnormalities directly on MRI machines, which provide crisp anatomical detail and don't involve radiation. But designing targeted imaging agents for MRI requires tricky chemical engineering. Huge quantities of magnetic material have to bind to a body target in order to generate a signal strong enough for an MRI to detect. (PET tracers require only tiny amounts of radioactivity to create a good signal, making the chemistry simpler.)
Kereos, an upstart shop in St. Louis, Mo., solves this by using 200-nanometer droplets of inert perfluorocarbons as molecular pincushions to hold a payload of up to 100,000 gadolinium molecules. To this the company attaches a smart drug that clamps on to a receptor called alpha(v)beta(3) integrin, which is abundant on tumor blood vessels. Kereos predicts the resulting drug will reliably "light up" tumors as small as 1 millimeter in diameter on MRI versus 5 millimeters for today's scans. "There's nothing out there today that can find 1- and 2-millimeter tumors," says Chief Executive Robert Beardsley. The nanodroplets also can be used to deliver concentrated doses of the chemo drug Taxol directly to tumors, bypassing healthy tissue. Human trials of both versions are slated for next year.
Further along is a nanoparticle that helps MRIs spot tiny clumps of tumor cells that have spread to the lymph nodes. It's already at the Food & Drug Administration for approval, but the FDA has delayed a ruling and requested more data. Devised by researchers at Massachusetts General Hospital and Advanced Magnetics, a publicly held outfit in Cambridge, Mass., the nanoparticle consists of balls of 8,000 iron molecules held together with a sugary coating. About half the size of a virus, the nanoparticles are sucked up by healthy lymph nodes--but not by malfunctioning cancerous ones. In a test on 80 prostate cancer patients, the nanoparticles enabled MRI scans to spot more than 95% of lymph-node metastases (confirmed later by biopsies). Old MRI scans could find fewer than half of them.
But how to turn these advances into a profitable business? The new imaging may have to go beyond diagnosing only symptomatic patients to find a bigger market, as a routine test akin to cholesterol screening in millions of healthy people. To accelerate the imaging revolution, researchers say, the FDA should adopt a sleeker and less-costly approval process for new agents. To that recipe add a dollop of magic:a few big successes in human trials to prove their health-altering potential.
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