Gene Key to Taste Bud Development Identified

Gene key to taste bud development identified

DURHAM, N.C. - Scientists have identified a gene that controls the development of taste buds.

The gene, SOX2, stimulates stem cells on the surface of the embryonic tongue and in the back of the mouth to transform into taste buds, according to the researchers. Stem cells are immature cells that can develop into several different cell types depending on what biochemical instructions they receive.

"Not only did we find that SOX2 is crucial for the development of taste buds, but we showed that the amount of SOX2 is just as important," said Brigid Hogan, Ph.D., chair of the Duke University Medical Center Department of Cell Biology and senior member of the research team. "If there isn't enough SOX2 present, or if there is too much, the stem cells will not turn into taste buds."

The researchers made their discovery in mice, but they believe the same process occurs in humans.

According to the researchers, the findings will help scientists better understand how the behavior of certain stem cells is controlled. The SOX2 gene is already known to be crucial in controlling whether embryonic stem cells remain undifferentiated and whether stem cells in the brain, eye and inner ear differentiate into specialized nerve cells.

Taste bud cells, much like skin cells, continually slough off and are replaced by new ones. So the new findings not only provide insights into the interactions between SOX2 and tongue stem cells during embryonic development, but also into how stem cells continue to operate in adults, the researchers said.

The researchers published the findings in the October 2006 issue of the journal Genes and Development. The work was supported by the National Institutes of Health.

Their findings were entirely serendipitous, Hogan said.

"In my laboratory, we were studying the role of SOX2 in the development of the lung, esophagus and the gut in embryonic mice" she said. "We were quite surprised when we accidentally found the gene's role to be so pronounced in the developing tongue."

The particular strain of mice that Hogan and her colleagues use had been developed by Larysa Pevny, Ph.D., a geneticist and developmental neurobiologist at the University of North Carolina at Chapel Hill, who is co-author with Hogan of the journal report. In engineering her new mouse strain for studying stem cells in the nervous system, Pevny combined the SOX2 gene with another gene, derived from jellyfish, and inserted the combination into the animals' chromosomes. She selected the added gene for its capacity to produce a special protein, called enhanced green fluorescent protein, that glows green when exposed to ultraviolet light.

"When we shine light on tissue from these animals, any cell that is expressing SOX2 will fluoresce, or light up," Pevny explained. "This allows us to directly visualize those areas where SOX2 is active. It is a very powerful tool."

In their work, Hogan and her colleagues use this fluorescence marker as a tool for tracking the activity of SOX2 in the esophagus, among other sites. As they worked with the mice, they noticed that specific areas on the tongue and in the back of the mouth lit up, in addition to areas in the esophagus. Further studies, Hogan said, confirmed that SOX2 was present in high amounts during the development of taste buds.

In another set of experiments, Hogan's team used another variant of the mouse strain made by Pevny in which the SOX2 gene was altered to produce only low levels of SOX2. In these animals, the stem cells in the tongue were not transformed into taste buds, she said. Instead, the cells became the "scaly" cells that cover the surface the tongue and help to direct food to the back of the mouth.

The new findings could lead to a better understanding of developmental disorders of the gut caused by mutations in the human SOX2 gene, Hogan said. For example, babies with such mutations can develop a tracheoesophageal fistula, a condition in which there is an abnormal connection between the windpipe and throat that requires surgery for correction.

Cancer patients receiving chemotherapy or radiation therapy often report the loss of taste during treatments. These therapies target cells that are dividing, making them effective in killing cancer cells but also causing the unwanted side effect of killing taste buds. When the cancer treatments end, the taste buds gradually return, Hogan said.

Scientists stop colon cancer growth in mice by blocking just one enzyme

Drug that inhibits inflammatory factor is already in human clinical trials for use in diabetes

GALVESTON, Texas - Texas researchers have discovered what may become a potent new weapon in the fight against colon cancer.

In cell culture experiments, scientists from the University of Texas Medical Branch at Galveston (UTMB) and the University of Texas at Arlington determined that stopping the activity of a single enzyme called aldose reductase could shut down the toxic network of biochemical signals that promotes inflammation and colon cancer cell growth.

In a dramatic demonstration of the potential of this discovery, they followed up this work with animal studies showing that blocking the production of aldose reductase halted the growth of human colon cancer cells implanted in laboratory mice.

"By inhibiting aldose reductase we were able to completely stop the further growth of colorectal cancer tumor cells," said UTMB professor Satish K. Srivastava, senior author of a paper about the discovery to be published Oct. 1 in the journal Cancer Research.

According to the federal Centers for Disease Control and Prevention, colon cancer is the country's second leading cancer killer. In 2002, the most recent year for which statistics are available, 70,651 men and 68,883 women were diagnosed with colon cancer in the United States; 28,471 men and 28,132 women died from the disease.

In a series of cell-culture experiments, Srivastava and his colleagues-including lead author and postdoctoral fellow Ravinder Tammali, assistant professor Kota V. Ramana, and Sharad S. Singhal and Sanjay Awasthi of the University of Texas at Arlington- investigated aldose reductase's role in colon cancer cell growth. First they stimulated colon cancer cells with growth factors, chemicals known to kick-start inflammatory chain reactions that encourage colon cancer cells to proliferate; this proliferation process then itself produces even more inflammation and cancer cell growth. (Chronic inflammation is strongly linked to the development of colon and other cancers.)

The researchers then blocked aldose reductase activity and checked the responses of known molecular links in the chain of colon cancer cell growth.

"In a nutshell, when we inhibited aldose reductase by using pharmacological inhibitors or genetic manipulations, all the inflammatory players were significantly blocked," Srivastava said. "We really understand this toxic signaling pathway much better now."

In their mouse experiments, the researchers implanted human colon cancer cells beneath the skin of "nude mice"-a hairless and immune-deficient variety commonly used in medical research. Tumor progression stopped completely in the mice treated with genetic material known as small interfering RNA (or "siRNA") that was engineered to prevent cells from making the aldose reductase enzyme.

The treated mice seemed unharmed by the procedure. In contrast, the untreated "control" animals experienced uncontrolled tumor growth.

As exciting as such results are, Srivastava pointed out, the distance between a brand-new procedure that works in nude mice and one that works in humans is considerable.

However, substantial research has already been done on developing drugs that inhibit aldose reductase in people, because the enzyme is also involved in causing such complications of diabetes as blindness and nerve damage.

Aldose reductase inhibitors might be in use against human colon cancer in a relatively short time, Srivastava said, since one candidate is already in phase 3 clinical trials in the United States for prolonged use in diabetes, and an aldose reductase inhibitor is already available for clinical use in Japan. Such drugs would likely be used after surgery as a "chemo-preventive" measure to keep cancer cells missed by surgery in check. "As far as I am aware, there is no other chemo-preventive agent that has been shown to be so effective in laboratory animals," the researcher said.

Stellar birth control in the early universe

New Haven, Conn. - An international team of astronomers based at Yale and Leiden University in The Netherlands found that "old stars" dominated many large galaxies in the early universe, raising the new question of why these galaxies progressed into "adulthood" so early in the life of the universe.

Every year only a handful of new stars are born out of the gas that fills the space between the stars in galaxies like the Milky Way. To account for the large number of stars in the Universe today, about 400 billion in the Milky Way alone, it was thought that the "stellar birth rate" must have been much higher in the past.

Surprisingly, in this study appearing in the October 2 issue of Astrophysical Journal, astronomers using the 8.1m Gemini telescope in Chile report that many of the largest galaxies in the Universe had a very low stellar birth rate even when the Universe was only about 20 percent of its present age.

"Our new results imply that the stars in many large galaxies were born when the Universe was in its infancy, in the first few billion years after the Big Bang," said team leader Mariska Kriek, a PhD student from Leiden University and Yale. "The results confirm what some astronomers had suspected - galaxies seem to have some method of 'birth control' that is very effective."

These new findings add to growing evidence that in big galaxies the formation of new stars was significantly suppressed after an initial period of vigorous activity. "These galaxies had a very violent early youth, but rose into stable adulthood well before many galaxies like the Milky Way were even in kindergarten," said Kriek."

The astronomers used the uniquely powerful Gemini Near Infrared Spectrograph, to analyze the light of distant galaxies simultaneously over many different wavelengths. They studied 20 galaxies so distant that their light had been traveling for nearly 11 billion years, or 80 percent of the age of the Universe.

Extremely massive black holes in the centers of galaxies may serve as 'cosmic contraceptives' in the early Universe, suppressing the birth of new stars. The blue beam of light in this Hubble Space Telescope image of the nearby galaxy M87 emanates from a black hole which has a mass exceeding a billion times that of the Sun. NASA and the Hubble Heritage Team (STScI/AURA)

"The unexpected finding is what was not found - we expected to see a prominent signal from ionized Hydrogen, the tell-tale signature of star birth. Remarkably, for nine of the twenty galaxies that we observed, this signature is not seen at all," said Pieter van Dokkum, associate professor of astronomy and physics at Yale University. "It gives a firm limit on the stellar birth rate in these objects."

One suggestion is that enormous black holes in the centers of large galaxies may be responsible for suppressing star formation. When material spirals into a black hole, huge amounts of energy are released and are rapidly injected into the galaxy's gas. This energy injection may dilute the gas sufficiently to prevent future star birth.

"Evidence for the presence of these black holes is seen in several of the galaxies studied, lending support to the idea that black holes serve as cosmic contraceptives in the young Universe," said van Dokkum.

Thirsty Giant

In Teeming India, Water Crisis Means Dry Pipes and Foul Sludge

By SOMINI SENGUPTA

NEW DELHI, Sept. 28 - The quest for water can drive a woman mad.

Ask Ritu Prasher. Every day, Mrs. Prasher, a homemaker in a middle-class neighborhood of this capital, rises at 6:30 a.m. and begins fretting about water.

It is a rare morning when water trickles through the pipes. More often, not a drop will come. So Mrs. Prasher will have to call a private water tanker, wait for it to show up, call again, wait some more and worry about whether enough buckets are filled in the bathroom in case no water arrives.

“Your whole day goes just planning how you’ll get water,” a weary Mrs. Prasher, 45, recounted one morning this summer, cellphone in hand and ready to press redial for the water tanker. “You become so edgy all the time.”

In the richest city in India, with the nation’s economy marching ahead at an enviable clip, middle-class people like Mrs. Prasher are reduced to foraging for water. Their predicament testifies to the government’s astonishing inability to deliver the most basic services to its citizens at a time when India asserts itself as a global power.

The crisis, decades in the making, has grown as fast as India in recent years. A soaring population, the warp-speed sprawl of cities, and a vast and thirsty farm belt have all put new strains on a feeble, ill-kept public water and sanitation network.

The combination has left water all too scarce in some places, contaminated in others and in cursed surfeit for millions who are flooded each year. Today the problems threaten India’s ability to fortify its sagging farms, sustain its economic growth and make its cities healthy and habitable. At stake is not only India’s economic ambition but its very image as the world’s largest democracy.

“If we become rich or poor as a nation, it’s because of water,” said Sunita Narain, director of the Center for Science and Environment in New Delhi.