New Worlds: A better DNA mapping technique

Since the sequencing of the human genome in 2001, all our genes – more than 20,000 in total – have been identified. But much information, such as where and when each is active, is still unknown. Next to each gene sits a short DNA segment, and the activity of this regulatory segment determines whether the gene will be turned on, where and how strongly. These short regulatory segments are just as – if not more – important than the genes themselves.

Indeed, 90 percent of the mutations that cause disease occur in these regulatory areas. They are responsible for the proper development of tissues and organs, determining – for example – that eye cells, and only eye cells, contain light receptors, while only pancreatic cells produce insulin. Clearly, a deeper understanding of this regulatory system, its mechanisms and possibilities for malfunction may lead to advances in biomedical research, especially in developing targeted therapies for individual patients.

In spite of their importance, the “regulatory code” is not well understood. To address this problem, a research team led by Dr. Ido Amit of the Weizmann Institute of Science’s immunology department together with scientists Manuel Garber, Nir Yosef and Aviv Regev from the Broad Institute in Massachusetts, and Nir Friedman of the Hebrew University of Jerusalem, developed an advanced automated system for mapping these sites, and then used this system to uncover important principles regarding how these regulatory elements function.

Among other things, their study, which recently appeared in Molecular Cell, revealed a hierarchical structure for the regulatory code. By mapping a large number of regulatory factors, the team revealed an overall plan for gene regulation as well as the intimate details of the mechanisms involved in the immune response. The process used for the past 30 years to map regulatory elements has been complicated, complex and labor-intensive, requiring huge scientific consortiums to accomplish the task. With the new method, just a handful of researchers were able to conduct a study on a similar scale to the mega-team ones, and in a fraction of the time.

Their highly efficient, automated method enabled Amit and his team to measure a large number of regulatory proteins and their binding sites in parallel. They exposed immune cells to bacteria – setting the stage for gene activation – and then traced the actions of several dozen different regulatory proteins known to play a role in the immune response over four points in time.

Not only were the researchers able to identify the binding locations of each and the genes they activate, but the levels of activation and the mechanisms employed.

One of their more significant findings was that the actions of these regulatory factors can be neatly classified into three levels in a sort of regulatory hierarchy. In the bottom tier are those factors that create the rough divisions into main cell types by directing cell differentiation. These factors are the “basic identity” guides that can, on their own, determine whether a cell will have the characteristics of a muscle cell or a nerve cell, for example. On the second tier are the regulatory factors that determine a cell’s sub-identity, which they do by controlling the strength of a gene’s expression. These factors are in charge of producing closely-related sub-types, for instance, muscle fibers that are either smooth or striated, or closely- related immune cells. Regulatory factors in the third tier are even more specialized, affecting the expression of certain genes in response to signals from outside the cell, such as bacterial invaders, hormones and hunger pangs.

They hope that understanding the ins and outs of the regulatory code will help researchers to understand and predict how diseases arise and progress due to malfunctions in regulatory mechanisms.

In the future, understanding the regulatory program may lead to advances in rehabilitative medicine. Regulatory mechanisms could be used to redirect the differentiation of a patient’s cells, which could then be re-implanted, thus avoiding the problems inherent in using donor cells.

“The new method for mapping the gene’s regulatory plan may open new vistas for investigating all sorts of biological processes, including the system failures that occur in disease,” Amit concludes.

CLEANING UP WITH CHOCOLATE

To the afficionado of sweets, it would seem to be a waste, but researchers at the University of Southern Mississippi have developed a new oil-spill dispersant made from ingredients found in ice cream, chocolate and peanut butter. The discovery was reported at a recent meeting of the American Chemical Society.

With concerns about the possible health and environmental effects of oil dispersants in the various gasoline spills around the world, new dispersants are needed that can be made from edible ingredients and can both break up oil slicks and keep oil from sticking to the feathers of birds.

“Each of the ingredients in our dispersant is used in common food products like peanut butter, chocolate and whipped cream,” said Dr. Lisa K. Kemp. “Other scientists are working on new oil dispersants and absorbents, but nothing that’s quite like ours. It not only breaks up oil but prevents the deposition of oil on birds and other objects, like the ingredients in laundry detergent keep grease from redepositing on clothing in the rinse cycle. Birds can sit in slicks of the dispersed oil, they can dive through it and take off and flap their wings, and the oil will fall off.”

The new dispersant is based on scientific principles established decades ago during the development of modern laundry detergents. One ingredient, for instance, is a special polymer that sticks to the surface of oil droplets to keep them from sticking to the feathers of sea birds. Similar polymers in laundry detergents keep oil and grease removed during the wash cycle from getting back on clothing during the rinse cycle.

When detergents are used to remove oil that has coated fur or feathers, it defeats their natural waterproofing effect, leaving birds less buoyant and more susceptible to hypothermia. Birds can also ingest the oil as they try to clean themselves, causing internal damage.

Another important advantage, Kemp noted, is the ease of quickly obtaining large amounts of ingredients for making the dispersant at reasonable cost. She envisioned agencies like the US Coast Guard keeping small amounts on hand for first response, with larger quantities being quickly made as necessary.