Saturday, August 28, 2010

NANOSCALE DNA SEQUENCING COULD SPUR REVOLUTION IN PERSONAL HEALTH CARE

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In experiments with potentially broad health care implications, a research team led by a University of Washington physicist has devised a method that works at a very small scale to sequence DNA quickly and relatively inexpensively.

That could open the door for more effective individualized medicine, for example providing blueprints of genetic predispositions for specific conditions and diseases, such as cancer, diabetes or addiction.

"The hope is that in 10 years people will have all their DNA sequenced and this will lead to personalized, predictive medicine," said Jens Gundlach, a UW physics professor and lead author of a paper describing the new technique published the week of Aug. 16 in the Proceedings of the National Academy of Sciences.

The technique creates a DNA reader that combines biology and nanotechnology using a nanopore taken from Mycobacterium smegmatis porin A. The nanopore has an opening 1 billionth of a meter in size, just large enough to measure a single strand of DNA as it passes through.

The scientists placed the pore in a membrane surrounded by potassium-chloride solution. A small voltage was applied to create an ion current flowing through the nanopore, and the current's electrical signature changed depending on the nucleotides traveling through the nanopore. Each of the nucleotides that are the essence of DNA -- cytosine, guanine, adenine and thymine -- produced a distinctive signature.

The team had to solve two major problems. One was to create a short and narrow opening just large enough to allow a single strand of DNA to pass through the nanopore and for only a single DNA molecule to be in the opening at any time. Michael Niederweis at the University of Alabama at Birmingham modified the M. smegmatis bacterium to produce a suitable pore.

The second problem, Gundlach said, was that the nucleotides flowed through the nanopore at a rate of one every millionth of a second, far too fast to sort out the signal from each DNA molecule. To compensate, the researchers attached a section of double-stranded DNA between each nucleotide they wanted to measure. The second strand would briefly catch on the edge of the nanopore, halting the flow of DNA long enough for the single nucleotide to be held within the nanopore DNA reader. After a few milliseconds, the double-stranded section would separate and the DNA flow continued until another double strand was encountered, allowing the next nucleotide to be read.

The delay, though measured in thousandths of a second, is long enough to read the electrical signals from the target nucleotides, Gundlach said.

"We can practically read the DNA sequence from an oscilloscope trace," he said.

Besides Gundlach and Niederweiss, other authors are Ian Derrington, Tom Butler, Elizabeth Manrao and Marcus Collins of the UW; and Mikhail Pavlenok at Alabama-Birmingham.

The work was funded by the National Institutes of Health and its National Human Genome Research Institute as part of a program to create technology to sequence a human genome for $1,000 or less. That program began in 2004, when it cost on the order of $10 million to sequence a human-sized genome.

The new research is a major step toward achieving DNA sequencing at a cost of $1,000 or less.

"Our experiments outline a novel and fundamentally very simple sequencing technology that we hope can now be expanded into a mechanized process," Gundlach said.

(Photo: Ian Derrington)

University of Washington

DANGEROUS BACTERIUM HOSTS GENETIC REMNANT OF LIFES DISTANT PAST

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Within a dangerous stomach bacterium, Yale University researchers have discovered an ancient but functioning genetic remnant from a time before DNA existed, they report in the August 13 issue of the journal Science.

To the surprise of researchers, this RNA complex seems to play a critical role in the ability of the organism to infect human cells, a job carried out almost exclusively by proteins produced from DNA’s instruction manual.

“What these cells are doing is using ancient RNA technology to control modern gene expression,” said Ron Breaker, the Henry Ford II Professor of Molecular, Cellular and Developmental Biology at Yale, investigator for the Howard Hughes Medical Institute and senior author of the study.

In old textbooks, RNA was viewed simply as the chemical intermediary between DNA’s instruction manual and the creation of proteins. However, Breaker’s lab has identified the existence and function of riboswitches, or RNA structures that have the ability to detect molecules and control gene expression – an ability once believed to be possessed solely by proteins. Breaker and many other scientists now believe the first forms of life depended upon such RNA machines, which would have had to find ways to interact and carry out many of the functions proteins do today.

The new paper describes the complex interactions of two small RNA molecules and two larger RNA molecules that together influence the function of a self-splicing ribozyme, a structure many biologists had believed had no role other than to reproduce itself. The new study, however, suggests that in the pathogenic stomach bacterium Clostridium difficile, this RNA structure acts as a sort of sensor to help regulate the expression of genes, probably to help the bacterium manipulate human cells.

“They were though to be molecular parasites, but it is clear they are being harnessed by cells to do some good for the organism,” Breaker said.

This is the sort of RNA structure that would have been needed for life exist before the evolution of double-stranded DNA, with its instruction book for proteins that carry out almost all of life’s functions today. If proteins are necessary to carry out life’s functions, scientists need to explain how life arises without DNA’s recipe. The answer to the chicken or egg question is RNA machines such as the one identified in the new study, Breaker said.

“A lot of sophisticated RNA gadgetry has gone extinct but this study shows that RNA has more of the power needed to carry out complex biochemistry,” Breaker said. “It makes the spontaneous emergence of life on earth much more palatable.”

Yale University

MODERATE DRINKING, ESPECIALLY WINE, ASSOCIATED WITH BETTER COGNITIVE FUNCTION

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A large prospective study of 5033 men and women in the Tromsø Study in northern Norway has reported that moderate wine consumption is independently associated with better performance on cognitive tests.

The subjects (average age 58 and free of stroke) were followed over 7 years during which they were tested with a range of cognitive function tests. Among women, there was a lower risk of a poor testing score for those who consumed wine at least 4 or more times over two weeks in comparison with those who drink < 1 time during this period The expected associations between other risk factors for poor cognitive functioning were seen, i.e. lower testing scores among people who were older, less educated, smokers, and those with depression, diabetes, or hypertension.

It has long been known that "moderate people do moderate things." The authors state the same thing: "A positive effect of wine . . . could also be due to confounders such as socio-economic status and more favourable dietary and other lifestyle habits.

The authors also reported that not drinking was associated with significantly lower cognitive performance in women. As noted by the authors, in any observational study there is the possibility of other lifestyle habits affecting cognitive function, and the present study was not able to adjust for certain ones (such as diet, income, or profession) but did adjust for age, education, weight, depression, and cardiovascular disease as its major risk factors.

The results of this study support findings from previous research on the topic: In the last three decades, the association between moderate alcohol intake and cognitive function has been investigated in 68 studies comprising 145,308 men and women from various populations with various drinking patterns. Most studies show an association between light to moderate alcohol consumption and better cognitive function and reduced risk of dementia, including both vascular dementia and Alzheimer's Disease.

Such effects could relate to the presence in wine of a number of polyphenols (antioxidants) and other micro elements that may help reduce the risk of cognitive decline with ageing. Mechanisms that have been suggested for alcohol itself being protective against cognitive decline include effects on atherosclerosis ( hardening of the arteries), coagulation ( thickening of the blood and clotting), and reducing inflammation ( of artery walls, improving blood flow).

Boston Medical Center

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