Scientists discover why teeth form in a single row

A system of opposing genetic forces determines why mammals develop a single row of teeth, while sharks sport several, according to a study published today in the journal Science. When completely understood, the genetic program described in the study may help guide efforts to re-grow missing teeth and prevent cleft palate, one of the most common birth defects.

Gene expression is the process by which information stored in genes is converted into proteins that make up the body's structures and carry its messages. As the baby's face takes shape in the womb, the development of teeth and palate are tightly controlled in space and time by gene expression. Related abnormalities result in the development of teeth outside of the normal row, missing teeth and cleft palate, and the new insights suggest ways to combat these malformations.

The current study adds an important detail to the understanding of the interplay between biochemicals that induce teeth formation, and others that restrict it, to result in the correct pattern. Specifically, researchers discovered that turning off a single gene in mice resulted in development of extra teeth, next to and inside of their first molars. While the study was in mice, past studies have shown that the involved biochemical players are active in humans as well.

"This finding was exciting because extra teeth developed from tissue that normally does not give rise to teeth," said Rulang Jiang, Ph.D., associate professor of Biomedical Genetics in the Center for Oral Biology at the University of Rochester Medical Center, and corresponding author on the Science paper. "It takes the concerted actions of hundreds of genes to build a tooth, so it was amazing to find that deleting one gene caused the activation of a complete tooth developmental program outside of the normal tooth row in those mice. Finding out how the extra teeth developed will reveal how nature makes a tooth from scratch, which will guide tooth regeneration research."

Why Extra Teeth Formed

When we lose our baby teeth, the permanent teeth grow in to replace them, but permanent teeth when lost are lost for good. U.S. adults aged 20 years and older are missing an average of four teeth due to gum disease, trauma or congenital defects. Tooth loss makes chewing difficult, causes speech problems, accelerates oral disease, and disfigures the face. Current treatments for missing teeth include dentures or dental implants, but each procedure comes with disadvantages. The idea of growing teeth to replace missing ones has captured the imaginations of scientists, with many labs investigating ways to regenerate teeth.

In the current study, Jiang and colleagues generated mice that lacked the oddskipped related-2 (Osr2) gene, which encodes one of many transcription factors that turn genes on or off. "Knocking out" (deleting) the Osr2 gene resulted in cleft palate, a birth defect where the two halves of the roof of the mouth fail to join up properly, leaving a gap. Secondly, and surprisingly, the Osr2 "knockout" mice developed teeth outside of the normal tooth row. Jiang decided to focus his research first on the effect of Osr2 on teeth patterning (vs. cleft palate) because much more was known at the time about teeth development pathways.

Although teeth usually do not become visible until after birth, their formation starts early in development. Teeth develop from the epithelium and mesenchyme, two key tissue layers within the mammalian embryo. The first sign of tooth development in mammals is the thickening of the epithelium along the jaw line to form a band of cells called the dental lamina. Because all teeth subsequently form from the dental lamina, the assumption was that some special quality of epithelial cells there made them "tooth competent." Classical experiments, however, found that the developing tooth mesenchyme was capable of inducing tooth formation from epithelial tissues that normally would not participate in tooth development. Researchers confirmed that it was indeed the mesenchyme that carried tooth initiation signals later in development, but how those signals were restricted to the area beneath the tooth row was unknown.

Past studies in other labs had shown bone morphogenic protein 4 (BMP4) to be an important factor for the initiation of teeth, and that a protein called Msx1 amplifies the BMP4 tooth-generating signal. Jiang and colleagues suggested for the first time that some unknown factor was restricting the growth of teeth into one row by opposing the Bmp4 signal.

The current study provides the first solid proof that the precise space where mammals can develop teeth (the "tooth morphogenetic field") is shaped and restricted by the effect of Osr2 on the expression of the Bmp4 gene within the mesenchymal cell layer. Jiang's team has shown not only that removing the Osr2 gene results in extra teeth outside of the normal row, but also that Osr2 is expressed in increasing concentration in the jaw mesenchyme as you move from the cheek toward the tongue in the mouse embryo, the exact opposite of the BMP4 concentration gradient. Osr2 restricts Bmp4 expression to the tooth mesenchyme under the dental lamina, and in Osr2's absence, Bmp4 gene expression expands into the jaw mesenchyme outside of the tooth row.

A second major finding of the study backs up another emerging theory which holds that careful regulation of competing pro- and anti-tooth initiation signals controls how mammalian teeth come one by one in sequence. As each tooth develops, something must prevent it from forming too close to the next or mammals would have no gaps between their teeth. When this mechanism occasionally falters, adjacent teeth come in fused together. Since evolution is not perfect, wisdom teeth (third molars) often come in too close to their predecessors, and must be pulled to make space.

Jiang and colleagues also engineered a group of mice with both the Osr2 and Msx1 genes removed. While mice without Msx1 failed to grow any teeth, mice lacking both Msx1 and Osr2 grew the first molars, but no additional teeth. Thus, without Osr2, enough BMP4 was expressed for the first molar teeth to grow, but without Msx1, the BMP4 signal was not amplified to the point where it could kick off the next tooth in the row. With these results, Jiang argues that BMP4 cooperates with other factors to create a temporary zone around each tooth where no other tooth can grow. When the tooth gets closer to maturity, Msx1 overwhelms decreasing levels of inhibitory factors to start the BMP4-driven development of the next tooth. Since the jaw is growing at the same time teeth are forming, it follows that each tooth must also receive signals that enough jaw has grown in for the next tooth to start forming atop it.

The implications of the current results may go beyond tooth development, researchers said. Thanks to the work of Jiang and others, some of the biochemical pathways involved in cleft lip/cleft palate development are now recognized, and may include BMP4, Msx1 and OSR2 as well as several others. In humans, Msx1 mutations have been linked with cleft lip/palate and with the failure to develop one or more teeth. In the next phase of the team's work, researchers will look at what other factors may be regulated by Msx1 and Osr2 to begin pinpointing the genetic network that controls teeth patterning and palate development. Their goal is to manipulate stem cells to treat malformations and to develop prevention strategies for cleft palate (e.g. the inclusion of folic acid in prenatal vitamins prevents neural tube defects in some cases). Cleft lip/palate occurs one in 700 live births.

Along with Jiang, the work was led by Zunyi Zhang and Yu Lan within the Center for Oral Biology and Department of Biomedical Genetics at the Medical Center. Yang Chai collaborated on the effort from the Center for Craniofacial Molecular Biology at University of Southern California School of Dentistry in Los Angeles. The work was sponsored by the National Institute of Dental and Craniofacial Research, part of the National Institutes of Health.

"Beyond medical applications, our results suggest that diversity in the number of tooth rows across species may be due to evolutionary changes in the control of the BMP4/Msx1 pathway," Jiang said. "In mammals, Osr2 suppresses this pathway to restrict teeth within a single row."

Source: University of Rochester Medical Center

Psychologists shed light on origins of morality

In everyday language, people sometimes say that immoral behaviours "leave a bad taste in your mouth". But this may be more than a metaphor according to new scientific evidence from the University of Toronto that shows a link between moral disgust and more primitive forms of disgust related to poison and disease.

"Morality is often pointed to as the pinnacle of human evolution and development," says lead author Hanah Chapman, a graduate student in the Department of Psychology. "However, disgust is an ancient and rather primitive emotion which played a key evolutionary role in survival. Our research shows the involvement of disgust in morality, suggesting that moral judgment may depend as much on simple emotional processes as on complex thought." The research is being published in Science on February 27, 2009.

In the study, the scientists examined facial movements when participants tasted unpleasant liquids and looked at photographs of disgusting objects such as dirty toilets or injuries. They compared these to their facial movements when they were subjected to unfair treatment in a laboratory game. The U of T team found that people make similar facial movements in response to both primitive forms of disgust and moral disgust.

The research employed electromyography, a technique that uses small electrodes placed on the face to detect electrical activation that occurs when the facial muscles contract. In particular, they focused on movement of the levator labii muscle, which acts to raise the upper lip and wrinkle the nose, movements that are thought to be characteristic of the facial expression of disgust.

"We found that people show activation of this muscle region in all three situations - when tasting something bad, looking at something disgusting and experiencing unfairness," says Chapman.

"These results shed new light on the origins of morality, suggesting that not only do complex thoughts guide our moral compass, but also more primitive instincts related to avoiding potential toxins," says Adam Anderson, principal investigator on the project and the Canada Research Chair in Affective Neuroscience. "Surprisingly, our sophisticated moral sense of what is right and wrong may develop from a newborn's innate preference for what tastes good and bad, what is potentially nutritious versus poisonous."

Source: University of Toronto

Is HIV testing during labor feasible?

Cameroon is a sub-Saharan African country with high HIV rates yet many pregnant women do not know their HIV status. Research published in the open access journal BMC Pregnancy and Childbirth has shown that HIV testing during labour is a suitable way of improving detection rates and may help mothers and their infants receive appropriate antiretroviral treatment.

Eugene Kongnyuy of the Liverpool School of Tropical Medicine and his collaborators from the University of Yaounde I, Cameroon, investigated the acceptability of rapid HIV testing among 2413 women of unknown HIV status at four hospitals in the capital city, Yaounde. They found that 88.3% of the women were willing to accept HIV testing during labour. Furthermore, their study revealed a higher rate of HIV infection among women screened during labour (10.1%) than was previously estimated in a national health survey (6.8%) which, according to the authors, highlights the importance of HIV testing during labour.

About 3.2 million infants and young children worldwide are infected with HIV and in most cases the infection is a consequence of mother-to-child transmission (MTCT). Rapid HIV testing during labour or delivery represents the last opportunity for treatment before delivery to reduce MTCT. While this investigation has shown that HIV testing in the delivery room is feasible, it is nevertheless a challenging task especially in resource-constraint settings. The authors recommend "an opt-out approach for HIV testing during labour in Cameroon (i.e. women are informed that HIV testing will be routine during labour if HIV status is unknown but each person may decline to be tested). Such an approach will decrease the proportion of women who give birth with unknown HIV status and increase the number of mother-infant pairs who receive appropriate treatment for preventing MTCT of HIV".

The team propose that cost-effectiveness of HIV counselling and testing during labour is evaluated before the approach is implemented nationwide.

More information: Acceptability of intrapartum HIV counselling and testing in Cameroon, Eugene Kongnyuy, Enow Mbu, Francois Mbopi-Keou, Nelson Fomulu, Philip Nana, Pierre Tebeu, Rebecca Tonye and Robert Leke, BMC Pregnancy and Childbirth (in press), http://www.biomedcentral.com/bmcpregnancychildbirth/

Source: BioMed Central

Do doodle: Research shows doodling can help memory recall

Doodling while listening can help with remembering details, rather than implying that the mind is wandering as is the common perception. According to a study published today in the journal Applied Cognitive Psychology, subjects given a doodling task while listening to a dull phone message had a 29% improved recall compared to their non-doodling counterparts.

40 members of the research panel of the Medical Research Council's Cognition and Brain Sciences Unit in Cambridge were asked to listen to a two and a half minute tape giving several names of people and places, and were told to write down only the names of people going to a party. 20 of the participants were asked to shade in shapes on a piece of paper at the same time, but paying no attention to neatness. Participants were not asked to doodle naturally so that they would not become self-conscious. None of the participants were told it was a memory test.

After the tape had finished, all participants in the study were asked to recall the eight names of the party-goers which they were asked to write down, as well as eight additional place names which were included as incidental information. The doodlers recalled on average 7.5 names of people and places compared to only 5.8 by the non-doodlers.

"If someone is doing a boring task, like listening to a dull telephone conversation, they may start to daydream," said study researcher Professor Jackie Andrade, Ph.D., of the School of Psychology, University of Plymouth. "Daydreaming distracts them from the task, resulting in poorer performance. A simple task, like doodling, may be sufficient to stop daydreaming without affecting performance on the main task."

"In psychology, tests of memory or attention will often use a second task to selectively block a particular mental process. If that process is important for the main cognitive task then performance will be impaired. My research shows that beneficial effects of secondary tasks, such as doodling, on concentration may offset the effects of selective blockade," added Andrade. "This study suggests that in everyday life doodling may be something we do because it helps to keep us on track with a boring task, rather than being an unnecessary distraction that we should try to resist doing."

Drug improves mobility for some MS patients

The experimental drug fampridine (4-aminopyridine) improves walking ability in some individuals with multiple sclerosis (MS). That is the conclusion of a multi-center Phase 3 clinical trial, the results of which were published today in the journal The Lancet.

"This study indicates that fampridine could represent an important new way to treat multiple sclerosis and perhaps become the first drug to improve certain symptoms of the disease," said neurologist Andrew Goodman, M.D., chief of the Multiple Sclerosis Center at the University of Rochester Medical Center (URMC) and lead author of the study. "The data suggest that, for a sub-set of MS patients, nervous system function is partially restored while taking the drug."

The study evaluated a sustained-release formulation of the drug, Fampridine-SR, which is being developed by Acorda Therapeutics, Inc. The company, which funded the study, submitted a new drug application to the U.S. Food and Drug Administration earlier this month. Goodman has been a consultant and advisor to Acorda for its fampridine studies in MS.

Multiple sclerosis is a disease of the central nervous system and is the most common cause of neurological disability in young adults. Worldwide it is estimated that more than a million people are affected by MS which is typically characterized by recurrent relapses followed by periods of remission early in its course. The symptoms of the disease vary from person to person, but commonly consist of muscle weakness, gait difficulties, numbness or tingling in arms and legs, difficulty with coordination and balance, blurred vision, and slurred speech. Over time, the effects of the disease tend to become more permanent and debilitating.

While the precise cause is unknown, it is understood that the immune system in individuals with MS attacks myelin, a fatty tissue in the central nervous system that wraps the fibers - or axons - that connect nerve cells. Similar to the insulation on an electrical wire, myelin allows for the efficient conduction of nerve impulses. When myelin is lost or damaged in the disease, signals between nerve cells are delayed, disrupted, or even blocked.

It is believed that fampridine improves the transmission of signals in the central nervous system of some MS patients by blocking potassium ion channels. These channels serve as gates on the surface of cells and regulate the normal electrical activity. In laboratory experiments involving nerve fibers with myelin that was damaged in a manner that mimics MS, scientists found that blocking these channels results in a recovery of signal conduction.

In the Phase 3 study published today, the effects of Fampridine-SR were tested in 301 adult MS patients at 33 locations in the U.S. and Canada over a 14-week period. Three quarters of the participants took the drug and the rest were given a placebo.

Typically, MS drugs have been evaluated based on the ability to prevent relapses. Because the goal of this study was to assess changes in function, the researchers instead sought to evaluate participants' mobility and muscle strength - as opposed to the disease process. In prior studies, Goodman and his URMC colleague, the late Steven Schwid, M.D., had validated new methods to measure changes in gait, or walking speed over distance. Employing these methods in The Lancet study, they found that 34.8% of those receiving the drug experienced an improvement (an average of about 25% increase) in the speed they could walk 25 feet compared to only 8.3% in the placebo group.

"During the course of the disease, many MS patients experience a decline in mobility and this disability has a major impact in terms of quality of life," said Goodman. "As a clinician, I can say that improvement in walking speed could have important psychological value; it may give individuals the potential to regain some of the independence that they may have lost in their daily lives."

Several other drugs have been approved to treat MS. These treatments either counter the nervous system inflammation that is a characteristic of the disease or suppress the immune system generally. While these drugs can be effective at preventing new relapses and slowing the progression of the disease, there are no treatments currently available that improve impaired function, such as mobility problems, for people with MS. Participants in the trial were allowed to continue to take most other medications for MS and researchers did not observe any negative interactions. However, a total of eleven patients (4.8%) in the fampridine-treated group discontinued the study due to side effects. Only two of these were considered by the investigators to be possibly related to treatment.

Source: University of Rochester Medical Center