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Of Hedgehogs and Cancer

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Indian scientists have discovered that a protein essential for growth turns hostile and causes cancer.

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Indian researchers in Bangalore have solved a puzzle that has been haunting scientists for a long time: how does a set of proteins that are crucial for the well-rounded development of organisms trigger cancers?

The work, spearheaded by scientists at the National Centre for Biological Sciences (NCBS), provides a significant insight into the erratic behaviour of Hedgehog proteins, named so because their absence gives embryos a prickly appearance.

The Hedgehog protein is aptly described as the construction supervisor of life, as it plays a critical role in directing an organism’s growth from a single fertilised egg to a collection of millions of structured, specialised cells. They ensure, among other things, that the hands and feet develop the right shape and number of digits, the heart is located on the left and not the right side of the body, and that we have two eyes and ears instead of one each.

For more than a decade, scientists have been trying to understand the protein’s role in deciding which group of cells should constitute a particular tissue or organ (such as nerves, muscles and liver). In the process they found that when the Hedgehog genes of lab animals were knocked off or mutated, the progenies were born without wings or limbs or eyes, clearly indicating their pivotal role in the overall growth of organisms.

But once an organism, including humans, grows into an able-bodied creature, the Hedgehog proteins are left with a minimal role to play, quite like a supervisor’s role that comes to an end once the building is up and occupied. Except that both need to be available for occasional repair jobs.

Earlier in the decade, a team of researchers led by Philip Beachy of the Johns Hopkins School of Medicine discovered that the protein is not entirely harmless: it causes medulloblastoma, one of the most common brain cancers in children. Since then researchers elsewhere have found the Hedgehog’s involvement in cancers of several other organs — small cell lung cancer, pancreatic and prostrate cancers and so on.

Over the years, it has become clear to scientists that in order to be “mischievous,” the Hedgehog proteins need to be hyperactive so that they are able to work on cells that are far away from their location. “How the Hedgehog proteins are able to ‘jump’ to cells far away from their parent cells remained a mystery for long,” says Neha Vyas, the first author of the paper that appeared in the prestigious journal Cell in the last week of June.

Vyas, a post doctoral student at Satyajit Mayor’s lab at NCBS, says they got interested in Hedgehog proteins for an entirely different reason. It is one of the few proteins in the body that requires cholesterol — a fatty substance often vilified for clogging arteries — for efficient functioning. Studies have shown that inadequate cholesterol levels in an expectant mother can mar the development of the baby in many ways. “Hence we were interested in the protein’s cholesterol link,” she says.

“It became clear to us that for the Hedgehog molecules to be able to act over a distance, two kinds of interactions are needed. The molecules need to come together and also collaborate with a group of special carriers which are required to ferry them across a long distance,”NCBS director K. VijayRaghavan, a co-author of the study, told KnowHow.

Clustering is a normal activity of the Hedgehog protein. But it leads to cancer when the Hedgehog is made when it should not be or cells act as if they are constantly “seeing” these proteins even when they are not, observes VijayRaghavan.

The scientists — including those from the University of Mysore and the Centre for Cellular and Molecular Biology in Hyderabad — found that Hedgehog proteins exploit the electrostatic interactions of amino acids on their surface for clustering, the first step in the long journey away from the parent cell. The scientists understood the mechanism by which Hedgehog proteins “move around” and also that deactivating a single amino acid on the protein’s surface puts an end to the formation of clusters and hence its unattended long haul.

“Identifying this initial step is of great help as it could be used to design an anti-cancer drug that could stall a mutant Hedgehog pathway,” says Vyas. “Drug designers could target it at the very source itself.”

However, developing a drug that can safely defuse the hyper Hedgehogs that cause the biological mayhem called cancer is not all that easy. Blocking the Hedgehog protein has to be very selective as it plays a role in the regeneration of organs and tissues.

“It is not clear how much regeneration in adults is dependent on Hedgehog proteins, but recent stem cell studies have shown that they are important,” says Mayor, the lead author. A cancer cell-targeted inhibitor should be the way to go, he sums up.

Sources: The Telegraph (kolkata, India)

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The Smell Secrets

Smells can be mapped and the relative distance between various odors determined:

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Odors waft up the nasal cavity to a patch of nerve cells above the eyes. From there, scent signals go to the olfactory bulb, higher brain areas involved in discrimination (frontal lobe), and primitive areas linked to emotions (limbic system).

Nearly 25 years ago, US physician and writer Lewis Thomas famously said of the sense of smell: “It may not seem a profound enough problem to dominate all the life sciences, but it contains, piece by piece, all the mysteries.” In humans, the olfactory sense can elicit vivid memories as much as it can evoke the imagination. But for most animals, smell is the primal sense that enables them to find food, detect predators and locate mates. From fruit flies to humans, one question has long puzzled researchers: how does the brain know what the nose is smelling?

A few years ago, US researcher Richard Axel and his student Lind Buck resolved this puzzle and won the 2004 Nobel Prize. In less than four years since, a team of Israeli scientists has shown that smells can be mapped and the relative distance between various odours determined.

The work which lays down the basic laws underlying our sense of smell has appeared in a recent issue of the journal Nature Methods. “This looks like an interesting attempt to classify odourants in relation to function. There is a need for being able to make such predictions with respect to odourants,” says Gaiti Hasan, a scientist at the National Centre for Biological Sciences, Bangalore, who works on the science of smell.

Unlike in smell, the physical attributes of vision and sound can be measured. For instance, one can easily know whether a particular musical note is different from another, because the ear can comprehend the difference in their frequencies. But no such physical relationship has been discovered for smells, partly because odour molecules are much more difficult to pin down than sound frequencies.

In order to create the map, researchers from the Weizmann Institute of Science, led by neurobiologist Noam Sobel, began working with 250 odourants. For each of these odourants, the scientists generated a list of around 1,600 chemical characteristics. Plotting these characteristics, they created a multi-dimensional map of smells that revealed the distance between one odour molecule and another.

Persistent research over the years, however, has helped the Israeli scientists tighten the list of traits needed to locate an odour on the map down to around 40. Subsequently, they checked to see whether the brain recognised this map as it recognises musical scales. Working with fruit flies to rats to honey bees, they studied the neural response patterns to smells and found that in all these species the closer any two smells were on the map, the more similar were the neural patterns.

Subsequently, the scientists tested 70 new smells by predicting the neural patterns that they would arouse. They later matched their predictions with experiments carried out at the University of Tokyo and found that their predictions closely matched the results of the experiments.

These findings lent support to the theory that, contrary to the commonly held view that smell is a subjective experience, there are universal laws governing the organisation of smells. These laws determine how our brain perceives them, says Sobel.

If the parameters they use to classify the odours are relatively simple, this is a significant achievement, Hasan told KnowHow. Hasan thinks such a map will help predict what the brain’s response to an unknown odourant would be.

In the past, scientists had tried to develop a method to measure smell. The method was rather crude and was based on the number of carbon atoms present in a particular compound. It failed miserably as scientists found that two compounds that have a similar chemical structure and differ by just one carbon atom elicited very different responses in the olfactory sensory neurons, the workhorse of the nose in detecting smells.

The smell map may be of potential interest to industry. For instance, characterising a smell on the basis of how the brain recognises it can enable it to be digitised and transferred via the computer in future. This could, for example, help the perfume industry develop superior perfumes.

You may click to see:->Secrets of smell land Nobel Prize

> Researchers Sniff Out Secrets of Smell

Sources: The Telegraph (Kolkata, India)