Find what you want. Multiple search engines. People & Public Records searches. Links and tips for finding stuff

By Denise Trunk

GAINESVILLE, Fla. - Fingers are key to the art of communication, whether it's a politician flashing a thumbs up to a cheering crowd or a bride displaying a diamond-bedecked ring finger.

Now scientists at the University of Florida and Harvard University have described how the art of cellular communication -- how cells "talk" and what happens when they stop -- plays a crucial role in normal limb development and the formation of digits in mice, a discovery that sheds light on the same process in people. The researchers detail their discovery in today's issue of the journal Cell.

Why the five fingers on a hand form into the sizes and shapes they do, and the fundamental mechanisms that cause some people to be born without fully formed fingers or extra fingers has been a mystery until now. Understanding the development process could someday help doctors correct defects before birth, or help regenerate limbs lost to accident or amputation, researchers say.

"Everybody's goal is to figure out the normal process well enough so then you can go back and maybe help a human," said Brian Harfe, Ph.D., a developmental biologist at UF's College of Medicine and the paper's lead author. "For example, if a baby is missing a pinkie, and we have learned enough about how this digit is formed in the first place, we might eventually be able to repair the defect by using what we know to induce a normal digit to grow."

The findings also could shed light on the development of the body's more-critical organs, he said.

"This is the first time anyone has figured out how the body regulates the size - not just of the limb, but possibly of other organs during development," he said.

The researchers studied cells in the mouse embryo limb bud that express an active gene called Sonic Hedgehog, which is essential for normal limb development. The gene expresses a protein that acts like a dispatcher, barking chemical orders to other molecules and initiating limb growth. The researchers followed the cells that expressed the gene and found that in many of these cells, the Sonic Hedgehog gene eventually stops sending its message and migrates to another part of the developing limb. These cells then form a "wedge" that directly blocks another important signaling pathway in the limb. When communications break down between key molecules, the signal for limb growth shuts down at the right time and a normal limb results.

Although the discovery was made in mice, scientists say the same pathway is believed to function in human cells.

Harfe, an assistant professor of molecular genetics and microbiology, studied mice bred to harbor a pair of visible genetic markers in Sonic Hedgehog-expressing cells. That enabled him to follow what happened to the cells as a limb developed, even after they stopped expressing the gene.

"Sonic Hedgehog turns off as you start to form the fingers," Harfe said. "Previously we had no way of following what happens to the cells that were expressing this gene once it turned off. We needed to design a way to follow the fates of these cells once they stopped expressing the Sonic Hedgehog gene. Once we did that, we learned that they formed this wedge and that the cells that formerly expressed Sonic Hedgehog actually form the last two fingers."

Harfe found that the length of time and the concentration of Sonic Hedgehog that cells were exposed to determined which digit the cells would form.

"There has always been a huge debate in the field as to how you get a pinkie as opposed to an index finger or a thumb," Harfe said. It is known that Sonic Hedgehog is expressed in a gradient, or in a decreasing concentration over distance, he said. "What we found is that both of the last two digits are formed directly from the cells that formerly expressed Sonic Hedgehog."

The cells that were exposed to the highest concentrations of Sonic Hedgehog, both because they were closest to it and for the longest periods of time, become the fourth and fifth digits in mice, akin to the ring and pinkie fingers in people. The digits farther away from the source of the gene form the second and third fingers, analogous to the index and middle fingers in people. The cells with no exposure to Sonic Hedgehog form the thumb, or first digit.

Sun Xin, an assistant professor of medical genetics at the University of Wisconsin at Madison, said, "I think Dr. Harfe's research described in the Cell paper is very important to the limb development field. The research allowed the authors to put forward a new model of how different structures form along the anterior/posterior axis of the limb. It will allow us to rethink the role of many other molecules involved in anterior/posterior patterning."

UF researchers screen relatives in hunt for type 1 diabetes risk factors

By Tom Nordlie GAINESVILLE, Fla. - The key to curing type 1 diabetes is likely to be a family affair, say University of Florida experts involved in an international research effort to probe the biologic basis for the disease's development. Researchers participating in the consortium known as Type 1 Diabetes TrialNet will screen relatives of patients with diabetes for markers in the blood that appear years before diabetes develops. The project aims to evaluate tens of thousands of people, tracking them over the years to see who acquires the disease and which factors play a role in causing the immune system to destroy insulin-producing beta cells in the pancreas. "Over the past 20 years, we've learned that type 1 diabetes is an immune-mediated disease occurring in genetically at-risk subjects," said Desmond Schatz, M.D., a professor and associate chairman of the department of pediatrics and the study's principal investigator at UF. "The disease can be predicted both in higher-risk relatives - one in 20 will develop it - and the low-risk general population - one in 300 will develop it. In TrialNet, we intend to study the precise mechanisms leading to the disease and institute therapies aimed at preventing and ameliorating the disease." Type 1 diabetes, formerly known as juvenile-onset diabetes, is a lifelong disease that accounts for 5 percent to 10 percent of all ,diagnosed cases of diabetes in the United States. Insulin is needed to convert blood glucose (sugar) into energy; without adequate insulin, the sugar in the blood isn't used and builds up. People with type 1 diabetes need daily insulin injections or an insulin pump to control blood sugar. Insulin replacement is not a cure for type 1 diabetes, it is only a means of controlling the disease. UF is one of 18 medical centers in the United States, Canada, Europe and Australia participating in Type 1 Diabetes TrialNet. This network of researchers, labs and facilities is dedicated to understanding the autoimmune process that leads to type 1 diabetes, preventing the disease and stopping its progression in those who have been newly diagnosed. At diagnosis, most people still have some of their insulin-producing beta cells. In time, however, the immune system destroys more of these cells, making it harder to control blood sugar levels. To be eligible for the TrialNet Natural History Study, one must be between 1 and 45 years of age and have a first-degree relative (a mother, father, brother, sister) with type 1 diabetes, or between 1 and 20 years of age with a second-degree relative (aunt, uncle, niece, nephew, cousin, grandparent) with type 1 diabetes. For research purposes, type 1 diabetes is defined as having developed before a person is 40 years of age and requiring insulin treatment within one year of diagnosis. The screening, available at no cost to study participants, involves a simple blood test for the autoantibodies that appear in at-risk people years before diabetes develops. After enrolling in the study, participants will be closely monitored for signs of type 1 diabetes and may be offered the opportunity to participate in studies that attempt to stop the disease process. A second TrialNet study will seek to delay or stop the immune destruction of beta cells, building on scientific knowledge gained from earlier research on drugs that treat other autoimmune diseases and prevent rejection of transplanted organs. Researchers at UF and five other medical centers will study patients ages 12 to 35 who received a diagnosis of type 1 diabetes within the previous three months. They will be randomly assigned to receive one of two drugs currently approved by the Food and Drug Administration for preventing organ rejection. Type 1 Diabetes TrialNet is funded by the National Institutes of Health, part of the U.S. Department of Health and Human Services. TheJuvenile Diabetes Research Foundation International and the American Diabetes Association also support TrialNet research. UF received a seven-year grant totaling $2 million for the various TrialNet studies, which began in September 2001. More information can be found at www.DiabetesTrialnet.org.