Biomedicine

Brainscope: Using a micro-endoscope implanted deep in the brain, researchers can see that the blood vessels feeding a tumor become distorted over time.
Credit: Reprinted by permission from Macmillan Publishers Ltd: Nature Medicine, advance online publication, 16 January 2011 (doi: 10.1038/sj.nm.2292)


A tiny endoscope keeps watch over a particular spot in the brain as it develops, or degenerates with disease

MIT Technology Review, February 2, 2011, by Emily Singer  —  A new type of micro-endoscope lets scientists watch nerve cells and blood vessels deep inside the brain of a living animal over days, weeks, or even months. A team led by Mark Schnitzer, associate professor of biology and applied physics at Stanford University, developed the endoscope—an optical instrument used to peer into the body—along with a system to insert it into the same spot time after time. This feature allowed scientists to track changes in minute features, such as the connections between cells in the brain.

“I think it will be a potent tool for tracking properties of cells over long periods of time in response to changes in the environment, over the course of learning, during aging or the progression of disease,” says Schnitzer. Some developmental and neurodegenerative diseases, for example, damage connections between neurons deep in the brain.

Of particular interest to neuroscientists is the hippocampus, an area deep in the brain that is crucial to memory. Previously, scientists had been able to look at regions such as this one in detail only with highly invasive methods and at a single point in time. “But a lot of brain disorders occur slowly,” says Schnitzer. “We don’t just want a snapshot, we want a time-lapse [movie] on a time scale that is relevant to the progression of the disease.”

Schnitzer’s team has been developing the micro-endoscope for several years. Dubbed the optical needle, it is 500 to 1,000 microns in diameter at its tip—about half the width of a grain of rice. While the device resembles a scaled-down version of the endoscopes now commonly used for surgery, the tiny lens is slightly different. The small size of the device means that a curved lens, typical in most microscopes, is impractical. Instead, its lens is made from a material that has internal variations in its refractive profile to guide rays of light.

In the new study, published online this month in Nature Medicine, researchers demonstrate that they can use the micro-endoscope to observe the same spot in the brain over time. They first implant a glass guide tube into an animal’s brain, placing it just above the area of interest, with a tiny microscope slide covering its tip. They can then insert the micro-endoscope into the tube, taking pictures of the cells using a standard two-photon microscope. After imaging, “you can pull the microneedle out, return the animal to its cage, then reinsert it [days or weeks] later and look again,” says Schnitzer.

Elly Nedivi, associate professor of neurobiology at MIT, says that being able to return to the same spot again and again may be one of the most important applications of the micro-endoscope. “You could use it to see if drugs are having an effect, such as whether a tumor is responding to treatment,” she says.

In their initial experiments, the Stanford researchers examined neural structures in the hippocampus, one of the only places in the brain where new neurons are born in adulthood. Schnitzer hypothesized that, because of this close proximity to new cells, these structures would change with the formation of new memories. “But that’s not what we found,” he says.  “After looking at more than 4,000 dendrites, we saw very few instances of change.”

In a second set of experiments designed to see how the brain changes in response to disease, Schnitzer’s team injected cancer cells into one side of a mouse’s brain. These cells then grew into tumors, allowing scientists to observe the changes in blood vessels that accompany cancer. Researchers found that the vessels on the cancerous side of the brain were unstable, and blood flow slowed down. The healthy side of the brain remained stable.

Emily Singer is the biomedicine editor of Technology Review.

Biomedicine

Mole scanner: Researchers at Vancouver General Hospital are testing a device that scans moles for signs of melanoma.
Credit: Verisante Technology

A new device that a doctor holds right over a mole uses laser light to determine if it’s melanoma

MIT Technology Review, February 2, 2011, by Veronique Greenwood  —   Detecting melanoma—the most lethal form of skin cancer—still relies on dermatologists eyeballing moles and deciding which ones warrant a biopsy. A new handheld device developed by scientists at the British Columbia Cancer Agency (BCCA) and licensed to Verisante Technology could provide instant information about the molecular makeup of moles.

The device, called the Verisante Aura, is held above a mole, and uses Raman spectroscopy, a technique that distinguishes molecules using their vibrational states, to scan for those whose relative concentrations are characteristic of melanoma. The device returns a verdict within seconds. Following a successful small clinical trial, Verisante is now analyzing the results of another trial with 1,000 moles. The company plans to seek approval from the U.S. Food and Drug Administration later this year.

For patients whose melanoma isn’t caught early, the life expectancy is less than a year. And rates of the disease are skyrocketing: the current estimate is that one in 58 Americans will get melanoma in their lifetime, up from one in 1,500 in 1935.

Work on the new device began in 2000, when dermatologists at BCCA were studying whether certain skin diseases could be identified by their unique spectral characteristics. In Raman spectroscopy, laser light changes the vibrational state of the bonds within molecules, which in turn causes a shift in the light that is reflected back to a sensor. The magnitude and direction of that shift reveal what molecules are in the sample, and at what concentration.

“We thought that because the Raman spectrum shift was a direct reflection of the molecules targeted, and because different skin lesions would have different molecules in differing concentrations, it should produce a diagnostic signature,” says co-inventor David McLean, a professor of medicine at the University of British Columbia. Even if the melanoma looks benign to the naked eye, the Raman spectrum signature will identify it.

The device compares a mole’s spectral signature to those in a database containing examples of melanoma and other skin diseases. It will help dermatologists decide whether to biopsy or not. And it could eventually be used by nondermatologists in areas where dermatologists are scarce, such as rural Canada, says McLean.

A danger that regulatory bodies will likely consider, however, is the chance for false negatives in such situations—that is, whether the device might dismiss a mole that turns out to be melanoma. Another concern is whether some dermatologists might use the device as a way to diagnose melanoma instead of using it to help them determine whether or not to do a biopsy. Other companies seeking to commercialize melanoma detection technology, including U.S.-based MelaSciences, which uses infrared scanning, are already facing such scrutiny at the regulatory level.

Whatever U.S. and Canadian regulatory agencies decide, there is a need for devices that can help identify melanoma, says Darrell Rigel, a professor of dermatology at NYU’s Langone Medical Center, and former president of the American Academy of Dermatology. “It’s a challenge to diagnose melanoma clinically. It’s subjective,” Rigel says. “And while it’s not so difficult with one spot, many people have lots of spots—how do you decide what to biopsy?”

Bacterial benefits: The bottom slide shows reduced inflammation
in the colon of a mouse treated with genetically engineered bacteria.
The top image shows the colon of an untreated animal, and the
middle image shows that of an animal treated with unmodified
bacteria.     Credit: PNAS

A twist on a traditional therapy shows promise for treating bowel disease

MIT Technology Review, February 2, 1011, by Emily Singer  —  Public interest in probiotics is on the upswing, if the glut of advertisements for probiotic yogurts—those with added doses of beneficial bacteria—is any evidence. Scientists are bringing this traditional therapy into the 21st century by genetically engineering the microbes to enhance their effect on the immune system. They hope the new bugs will ultimately help treat inflammatory bowel diseases such as Crohn’s disease and ulcerative colitis, as well as other disorders that result from an overactive immune system.

In research published today in the Proceedings of the National Academy of Sciences, scientists deleted a gene from the bacterium Lactobacillus acidophilus, which is commonly found in yogurt. Mansour Mohamadzadeh, associate professor of medicine at Northwestern University, and collaborators had previously shown that the enzyme this gene manufactures increases inflammation, a defining characteristic of Crohn’s disease and ulcerative colitis. But the unaltered form of the bacterium also triggered production of a beneficial immune molecule, IL-10m, which helps to regulate the immune system. The goal of engineering the microbes was to deliver the beneficial effects without the harmful ones.

When fed to mice with colitis and inflammation of the colon, the engineered bacteria prevented the weight loss and bloody diarrhea that typically accompanies this condition. In addition, the treated mice had 90 percent less inflammation in their colon tissue than did their untreated counterparts.

While probiotic foods and supplements are a huge industry, it’s unclear whether they actually help treat most gastrointestinal diseases. The research published today is part of a trend in microbiology to explore in rigorous detail the effects of probiotics and the mechanisms that underlie them.

“The concept [of probiotics] is wonderful, but the evidence of their [effectiveness] is fairly limited,” says Balfour Sartor, co-director of the Center for Gastrointestinal Biology and Disease at the University of North Carolina, who was not involved in the new study. Because probiotics are considered a food and not a drug, they are not regulated by the U.S. Food and Drug Administration, and therefore don’t require the large clinical tests that drugs do.

Inflammatory bowel disease is one of the prime areas of interest for probiotic treatment, but “there really has been little direct evidence that probiotics are effective in treatment or prevention of Crohn’s disease,” says Sartor. Some research suggests that two different probiotic formulations can help prevent recurrence of ulcerative colitis, he says. “But that’s just two out of thousands of formulations.”

Scientists still don’t know exactly how probiotic bacteria influence the gastrointestinal system, but previous research suggests several possible mechanisms. Beneficial bacteria might temporarily alter the ratio of good to bad bacteria that inhabit the intestine, or they might specifically block activity of bad bacteria. And probiotics seem to influence the immune system, “stimulating protective immune cells or blocking detrimental activities of immune cells,” says Sartor.

Mohamadzadeh’s team is focused on the activity of immune cells.  Researchers looked in detail at the molecular effects of the engineered bacteria and found that the production of regulatory immune cells, rather than of inflammatory immune cells, was enhanced. “When we treat mice with the new strain, we see more accumulation and generation of cells that produce regulatory proteins, which lure and generate regulatory T cells,” says Mohamadzadeh. The regulatory T cells, a type of immune cell, counteract the effects of harmful immune cells that attack the cells lining the gut, he says.

While the research is promising, Sartor cautions that “it’s a huge leap between animal models and disease.” Probiotic treatments “don’t always have the same effects in humans as they do in animals, and there is a big difference in showing protection in animal models [by treating the animals before symptoms occur] versus treating ongoing human disease.”

Mohamadzadeh says that before beginning clinical tests, he plans to study the roles of more kinds of surface proteins in the engineered bacteria, to determine which are helpful and which are harmful. If scientists can identify the molecules the bacteria make that help regulate the immune system, they may be able to develop drugs that have a similar effect. (It’s easier to modify and give controlled doses of chemical compounds than live bacteria, which can behave unpredictably once ingested.)

Mohamadzadeh’s team is also exploring engineered probiotics as a treatment for colon cancer. In preliminary studies in mice designed to mimic colon cancer, treatment with the modified bacteria reduced the number of polyps the animals developed by 90 percent. “We observed an average of just three small polyps in treated mice, compared to about 35 to 50,” he says.

He adds that the bacteria’s ability to reduce inflammation isn’t limited to the gut; the regulatory cells migrate throughout the body. That means the microbes may also be able to help treat other diseases linked to inflammation, such as rheumatoid arthritis and psoriasis.