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Wednesday, October 31, 2007Mice Mystery
Clinton T. Rubin knows full well that his recent results are surprising — that no one has been more taken aback than he. And he cautions that it is far too soon to leap to conclusions about humans. But still, he says, what if ... ?
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And no wonder, other scientists say. Dr. Rubin, director of the Center for Biotechnology at the State University of New York at Stony Brook, is reporting that in mice, a simple treatment that does not involve drugs appears to be directing cells to turn into bone instead of fat.
All he does is put mice on a platform that buzzes at such a low frequency that some people cannot even feel it. The mice stand there for 15 minutes a day, five days a week. Afterward, they have 27 percent less fat than mice that did not stand on the platform — and correspondingly more bone.
“I was the biggest skeptic in the world,” Dr. Rubin said. “And I sit here and say, ‘This can’t possibly be happening.’ I feel like the credibility of my scientific career is sitting on a razor’s edge between ‘Wow, this is really cool,’ and ‘These people are nuts.’”
The responses to his work bear out that feeling. While some scientists are enthusiastic, others are skeptical.
The mice may be less fat after standing on the platform, these researchers say, but they are not convinced of the explanation — that fat precursor cells are turning into bone.
Even so, the National Institutes of Health is sufficiently intrigued to investigate the effect in a large clinical trial in elderly people, said Joan A. McGowan, a division director at the National Institute of Arthritis and Musculoskeletal and Skin Diseases.
Dr. McGowan notes that Dr. Rubin is a respected scientist and that her institute has helped pay for his research for the past 20 years, but she does caution against jumping to conclusions.
“I’d call it provocative,” she said of the new result. “It says, ‘Keep looking here; this is exciting.’ But it is crucial that we don’t oversell this.” For now, she added, “it is a fundamental scientific finding.”
The story of the finding, which was published online and will appear in the Nov. 6 issue of Proceedings of the National Academy of Sciences, began in 1981 when Dr. Rubin and his colleagues started asking why bone is lost in aging and inactivity.
“Bone is notorious for ‘use it or lose it,’” Dr. Rubin said. “Astronauts lose 2 percent of their bone a month. People lose 2 percent a decade after age 35. Then you look at the other side of the equation. Professional tennis players have 35 percent more bone in their playing arm. What is it about mechanical signals that makes Roger Federer’s arm so big?”
At first, he assumed that the exercise effect came from a forceful impact — the pounding on the leg bones as a runner’s feet hit the ground or the blow to the bones in a tennis player’s arm with every strike of the ball. But Dr. Rubin was trained as a biomechanical engineer, and that led him to consider other possibilities. Large signals can actually be counterproductive, he said, adding: “If I scream at you over the phone, you don’t hear me better. If I shine a bright light in your eyes, you don’t see better.”
Over the years, he and his colleagues discovered that high-magnitude signals, like the ones created by the impact as foot hits pavement, were not the predominant signals affecting bone. Instead, bone responded to signals that were high in frequency but low in magnitude, more like a buzzing than a pounding.
That makes sense, he went on, because muscles quiver when they contract, and that quivering is the predominant signal to bones. It occurs when people stand still, for example, and their muscles contract to keep them upright. As people age, they lose many of those postural muscles, making them less able to balance, more apt to fall and, perhaps, prone to loss of bone.
“Bone is bombarded with little, teeny signals from muscle contractions,” Dr. Rubin said.
He discovered that in mice, sheep and turkeys, at least, standing on a flat vibrating plate led to bone growth. Small studies in humans — children with cerebral palsy who could not move much on their own and young women with low bone density — indicated that the vibrations might build bone in people, too.
Dr. Rubin and his colleagues got a patent and formed a company to make the vibrating plates. But they and others caution that it is not known if standing on them strengthens bones in humans. Even if it does, no one knows the right dose. It is possible that even if there is an effect, people might overdose and make their bones worse instead of better.
Some answers may come from the federal clinical trial, which will include 200 elderly people in assisted living. It is being directed by Dr. Douglas P. Kiel, an osteoporosis researcher and director of medical research at the Institute for Aging Research at Harvard. The animal work made him hopeful that the buzzing platforms would have an effect on human bones.
“This work is fascinating and very legitimate,” Dr. Kiel said.
But then Dr. Rubin reported that the mice were also less fat, which led to the revised plans to look for changes in body fat as well.
Dr. Rubin says he decided to look at whether vibrations affect fat because he knows what happens with age: bone marrow fills with fat. In osteoporosis, the bones do not merely thin; their texture becomes lacy, and inside the holes is fat. And a few years ago, scientists discovered a stem cell in bone marrow that can turn into either fat or bone, depending on what signal it receives.
No one knows why the fat is in bone marrow — maybe it provides energy for failing bone cells, suggests Dr. Clifford J. Rosen, director of the Maine Center for Osteoporosis Research and Education. And no one knows whether human fat cells ever leave the bone marrow and take up residence elsewhere.
But Dr. Rubin had an idea. “We thought, Wait a second,” he said. “If we are mechanically stimulating cells to form bone, what isn’t happening? We thought maybe these bone progenitor cells are driving down a decision path. Maybe they are not becoming fat cells.”
He paid a visit to Jeffrey E. Pessin, a diabetes expert at Stony Brook, and presented his hypothesis. Dr. Pessin laughed uproariously. He “almost kicked me out of his office,” as Dr. Rubin put it.
But when Dr. Rubin decided to go ahead anyway, Dr. Pessin joined in. Their hope was to see a small effect on body fat after the mice stood on the platforms 15 minutes a day, 5 days a week, for 15 weeks. Dr. Rubin was stunned by the 27 percent reduction.
“Talk about your jaw dropping,” he said.
Some obesity researchers, though, say there may be other reasons that the mice were less fat.
“It is a very intriguing paper,” said Claude Bouchard, an obesity researcher who is director of the Pennington Center for Biomedical Research at Louisiana State University. But he wondered whether the mice on the platform were simply burning more calories.
“It seems to me,” Dr. Bouchard said, “that putting myself in the body of a mouse, if I was on a platform that was vibrating 90 times a minute, I would try to adhere to the surface and not be thrown off. I would probably tense my legs a little bit. That is energy expenditure.”
Stress may be another factor, he added. Standing on the platform may have frightened the mice, and they might have become sick.