Science, Medicine, Technology


Skeleton key

We knew our bones were busy producing blood cells and platelets, storing and releasing calcium into the bloodstream, and protecting our squishy innards. Now Columbia scientists have discovered an entirely new function of the skeleton: They say it also acts as an endocrine organ, producing a hormone that helps us process sugar.

Hormones, which control everything from growth to metabolism to reproduction, typically come from our glands or sex organs; a few have been traced to the heart, abdominal organs, and skin. They weren’t known to come from bone, until now. A research team led by Gerard Karsenty, chair of the Department of Genetics and Development at Columbia’s College of Physicians and Surgeons, has found that osteocalcin, a hormone released by bone cells, directly regulates the metabolism of glucose in mice. Shortages of osteocalcin, the researchers say, seem to cause obesity and type 2 diabetes in the animals.

There is “no guarantee” that the hormone behaves similarly in humans, “but osteocalcin exists in humans,” Karsenty says. “It operates in a region where type 2 diabetes genes are known to be present, and its levels vary with sugar metabolism, so we are cautiously optimistic.” 

In mice, at least, osteocalcin controls blood sugar by increasing the proliferation of insulin-producing beta cells in the pancreas, signaling those beta cells to produce more insulin and triggering fat cells to release another hormone, called adiponectin, that enhances insulin sensitivity. Mice and men both rely on insulin to sweep sugar from the blood and into cells, where it is used as energy or stored as fat.

If osteocalcin has comparable effects on people, Karsenty says, its discovery could lead to a cure for the 20 million Americans with diabetes, in whom insufficient insulin levels can chronically elevate blood glucose, heightening the risk of heart disease, kidney failure, and blindness.

But the discovery that the skeleton interacts with other organs is stunning in itself, prompting scientists to reconsider the skeleton’s purpose. “It certainly has caused quite a stir,” Graham Williams, an endocrinology expert at Imperial College London, told the Web site Nature News recently. “People think it’s a novel idea, and likely to turn out to be a paradigm shift.”

Karsenty and his team had been searching for a skeletal hormone that communicates with fat since demonstrating in 2002 that leptin, a hormone produced by fat cells, is crucial to regulating bone mass. Given that most bodily systems work as feedback loops, if fat signals bone, it stood to reason that bone might also signal fat. Osteocalcin, already known to be lower in diabetics thanks to earlier studies investigating the link between diabetes and an increased incidence of bone fractures, was thrown into the mix of suspects.

The researchers found that mice genetically programmed to have high levels of osteocalcin don’t gain weight or become diabetic even when fed a high-fat diet, while mice manipulated to lack osteocalcin become fat, secrete less insulin and adiponectin, produce fewer beta cells, and develop type 2 diabetes.

Karsenty says his lab will continue to investigate the role of osteocalcin in glucose metabolism, in animals as well as humans, with an eye toward developing novel therapies for preventing obesity, type 2 diabetes, and related disorders.

The study was published in the August issue of the journal Cell.


Buzz kill

Scientists investigating a dramatic drop in the nation’s honeybee population over the past year have suspected as the cause everything from pesticides to extreme weather to cell phones interfering with bees’ navigation systems. But Columbia researchers say they’ve identified the real culprit: a bee pathogen first discovered in Israel three years ago.

Apiarists across the U.S. first noticed that large numbers of bees were missing last November. Curiously, beekeepers weren’t finding dead bees in or near their hives; rather, worker bees were flying off in search of nectar and simply vanishing. More than honey was at stake: Many commercial farmers rely on kept bees to pollinate fruit, vegetable, and nut crops because there aren’t enough wild honeybees to do the job. So they ship in hives on flatbed trucks to pollinate crops in bloom.

A team of scientists led by Penn State entomologist Diana Cox-Foster last winter enlisted Ian Lipkin, director of Columbia’s Jerome L. & Dawn Greene Infectious Disease Laboratory, to help investigate what they are calling Colony Collapse Disorder (CCD). Lipkin, an epidemiology professor who discovered the West Nile virus in 1999, doesn’t usually work with insects. But Cox-Foster persuaded him that the highly sophisticated genetic techniques he uses to isolate human pathogens could help solve the CCD riddle. With technology pioneered in his own laboratory for isolating microbes, as well as commercial DNA sequencing tools, Lipkin and his team screened for viruses, bacteria, parasites, and fungi in samples taken from vacated hives as well as from healthy ones.

The researchers found a bug called Israeli acute paralysis virus (IAPV) in all of the CCD hives tested except one. While that doesn’t prove the virus is the cause of CCD, Lipkin says it establishes a strong link. “At minimum, IAPV is a significant marker for bees and hives at risk for CCD,” he says.

Most experts, including Lipkin, believe that multiple causes are behind the phenomenon; autopsies of the few dead bees recovered from CCD hives have turned up numerous viruses, bacteria, fungi, and parasites. But IAPV appears to be the common denominator. It could be that IAPV wipes out colonies that are already immunosuppressed, Lipkin suggests.

To test his theory, researchers at Penn State and the U.S. Department of Agriculture now are introducing IAPV into healthy hives as well as hives with other problems to see under what conditions the colonies will fail. Lipkin’s lab is providing the IAPV samples for these follow-up studies and will participate in the data analyses.
The bees’ disappearing act continues, meanwhile. A quarter of the nation’s apiaries have already lost between 50 and 90 percent of their bees — totaling tens of billions of missing insects — and entomologists are reporting possible CCD cases in Europe, South America, and Asia, as well as Israel. Some experts worry this could become a global catastrophe, while others are more sanguine, noting that honeybees have gone missing before. In the last century, bee populations periodically experienced similar declines. Scientists are still trying to figure out whether CCD may be a repeat of these earlier die-offs, or if it represents a new and unprecedented threat to honeybees.

The good news is that if IAPV is definitively implicated as a cause of CCD, researchers think science and nature together may be able to outmaneuver it. Israeli researchers have found that some honeybees that have survived CCD have incorporated short segments of the virus’s DNA into their own DNA. “This integration confers resistance to the disease,” says Lipkin, whose findings appeared in the September issue of the journal Science. “Colonies of naturally emerging transgenic bees could be expanded and used to repopulate hives decimated by CCD.”


Glow mouse

Pharmaceutical companies today are spending millions of dollars developing fluorescent dyes that can be injected into mice and then made visible by shining an ordinary light through the animal, just as a child might peer into his hand with the help of a flashlight. Dyes that glom onto cancer cells, for instance, can reveal the size of a tumor, enabling researchers to monitor how it responds to medication. The imaging procedures are designed specifically for tiny lab animals, whose bodies are easily illuminated, so visible light does the trick — x-ray and MRI technology typically isn’t necessary.

A shortcoming of in vivo imaging techniques, however, is that the light that finds the dye shines right through internal organs, making them invisible even to the most highly sensitive cameras. “That makes it difficult to know exactly where the tumor is in relation to organs,” says Columbia biomedical engineering assistant professor Elizabeth Hillman, “especially because organs will shift slightly as the animals grow.”

Hillman thinks she’s solved this dilemma. Whereas current in vivo imaging techniques involve taking a single photograph to show where fluorescent dye eventually accumulates in an animal, Hillman has invented a way to record movies of the dye circulating throughout the animal. She says that the dye enters various organs at slightly different times, but that all parts of the liver, for example, fill up with dye together. By analyzing each pixel of every frame in her movie to determine when individual pixels show the presence of dye, Hillman can map the borders of every organ. She then creates color-coded images showing their locations.

“This will give researchers very cheap and simple anatomical overlays to reveal whether a tumor is touching the liver, the kidney, the gut, or all of them,” says Hillman. Her technology also could generate more definitive images of tumors. “Using current imaging techniques, the movement of dye in the animal’s body often creates noise in results because some of the dye might not have accumulated in the tumor when the photograph is taken,” she says. “By showing where the dye is moving, and in what tissues it is increasing, we can provide an extra level of information.”

Hillman’s study appeared in the September issue of the journal Nature Photonics.


Testy docs

Doctors commonly adjust their operating room techniques, causing some surgeries to be performed differently from hospital to hospital. “It’s not like with drugs, where the treatment is proven safe and then doesn’t change,” says Michael Parides, an associate clinical professor of biostatistics at Columbia University’s Mailman School of Public Health. “Surgeons are constantly making improvements, or at least what they think are improvements.”

How do researchers test the effectiveness of those changes? Patients must be assigned randomly to receive one procedure or another in a clinical trial, a type of study that is difficult to make happen when high-risk surgeries are involved. Although only volunteers participate, doctors and scientists have a hard time agreeing on what procedures to study, given their own entrenched ideas about which approaches are best and the vital consequences for patients.

To initiate such studies about cardiac procedures, the National Heart, Lung, and Blood Institute (NHLBI) recently awarded Columbia a five-year $23 million grant to lead a new research network. Eight institutions together will decide which cardiac surgeries should be examined. The trials may involve testing a common surgery against a newly approved procedure or testing two common procedures against each another. The Data Coordinating Center for Cardiothoracic Surgical Trials Network will be based at the Mailman School and Columbia’s College of Physicians and Surgeons.

One likely target of inquiry, says Parides, the project’s principal investigator, is how best to repair the heart’s mitral valve when clogged. When, for instance, should doctors perform a bypass operation rather than clean out  the valve?

As the hub of the research network, Columbia will participate in clinical trials it initiates. The network includes Duke University, the Cleveland Clinic, the Albert Einstein-Montefiore Medical Center, Emory University, the University of Virginia, the Montreal Heart Institute, and the University of Pennsylvania. Co-principal investigators on the project are Annetine Gelijns and Alan Moskowitz, both professors of health policy and management at the School of Public Health, and Deborah Ascheim, an assistant professor of medicine at the College of Physicians and Surgeons.

“This network will address the unanswered questions about which patients may benefit most from heart surgeries,” says Eric Rose, chairman of Columbia’s surgery department, “and when new technologies are appropriate.”


New starry night

A black hole is by definition invisible, a gravitational force so immense that even light cannot escape. How do we know it’s there? Envision a tornado: You don’t see its vortex, just the debris picked up around the edges. Astronomers, similarly, see cosmic material spiraling toward a black hole only before it enters, or more precisely, they detect heat energy that the material emits.

The most powerful black holes frustrate attempts at observation, however, because they grow in the most gaseous and dusty regions of the universe. The debris that surrounds and feeds these so-called supermassive black holes obscures from astronomers the action taking place near the holes themselves.

Columbia physics professor Charles Hailey has developed optics technology that could enable astronomers to study black holes that have never been seen clearly before, and even to identify new black holes billions of light-years away. He has designed the largest telescope ever for detecting hard x-rays, a type of energy generated at the edge of supermassive black holes and so powerful that it emanates out past the surrounding maelstrom.

Hailey expects to soon receive a $7 million to $10 million contract from NASA to fine-tune his technology and put it aboard a satellite to be launched in 2011 as part of NASA’s Nuclear Spectroscopic Telescope Array project. Hailey is the principal investigator for the program’s optics work.

“This will be an exploratory mission that will ask: How many black holes are out there? What are their sizes? What is their energy output?” says Hailey. “We should make major discoveries because our telescope will be 1000 times more sensitive to black holes than anything that’s ever gone into space.”