Monday, July 27, 2009

STUDY REVEALS MAJOR GENETIC DIFFERENCES BETWEEN BLOOD AND TISSUE CELLS

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Research by a group of Montreal scientists calls into question one of the most basic assumptions of human genetics: that when it comes to DNA, every cell in the body is essentially identical to every other cell. Their results appear in the July issue of the journal Human Mutation.

This discovery may undercut the rationale behind numerous large-scale genetic studies conducted over the last 15 years, studies which were supposed to isolate the causes of scores of human diseases.

Except for cancer, samples of diseased tissue are difficult or even impossible to take from living patients. Thus, the vast majority of genetic samples used in large-scale studies come in the form of blood. However, if it turns out that blood and tissue cells do not match genetically, these ambitious and expensive genome-wide association studies may prove to have been essentially flawed from the outset.

This discovery sprang from an investigation into the underlying genetic causes of abdominal aortic aneurysms (AAA) led by Dr. Morris Schweitzer, Dr. Bruce Gottlieb, Dr. Lorraine Chalifour and colleagues at McGill University and the affiliated Lady Davis Institute for Medical Research at Montreal’s Jewish General Hospital. The researchers focused on BAK, a gene that controls cell death.

What they found surprised them.

AAA is one of the rare vascular diseases where tissue samples are removed as part of patient therapy. When they compared them, the researchers discovered major differences between BAK genes in blood cells and tissue cells coming from the same individuals, with the suspected disease “trigger” residing only in the tissue. Moreover, the same differences were later evident in samples derived from healthy individuals.

“In multi-factorial diseases other than cancer, usually we can only look at the blood,” explained Gottlieb, a geneticist with McGill’s Centre for Translational Research in Cancer. “Traditionally when we have looked for genetic risk factors for, say, heart disease, we have assumed that the blood will tell us what’s happening in the tissue. It now seems this is simply not the case.”

“From a genetic perspective, therapeutic implications aside, the observation that not all cells are the same is extremely important. That’s the bottom line,” he added. “Genome-wide association studies were introduced with enormous hype several years ago, and people expected tremendous breakthroughs. They were going to draw blood samples from thousands or hundreds of thousands of individuals, and find the genes responsible for disease.

“Unfortunately, the reality of these studies has been very disappointing, and our discovery certainly could explain at least one of the reasons why.”

AAA is a localized widening and weakening of the abdominal aorta, and primarily affects elderly caucasian men who smoke, have high blood pressure and high cholesterol levels. It often has no symptoms, but can lead to aortic ruptures which are fatal in 90 per cent of cases.

If the mutations discovered in the tissue cells actually predispose for AAA, they present an ideal target for new therapies, and may have even wider therapeutic implications.

“This will probably have repercussions for vascular disease in general,” said Schweitzer, of McGill’s Department of Medicine. “We have not yet looked at coronary or cerebral arteries, but I would suspect that this mutation may be present across the board.”

Schweitzer is optimistic that this discovery may lead to new treatments for vascular disease in the near to medium term.

“The timeline might be five to 10 years,” he said. “We have to do in-vitro cell culture experiments first, prove it in an animal model, and then develop a molecule or protein which will affect the mutated gene product. This is the first step, but it’s an important step.”

(Photo: Mcgill U.)

McGill University

LONGEVITY PILL ON THE HORIZON?

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While applauding findings that an Easter Island compound extends the lives of middle-aged mice, University of Washington longevity researchers caution that healthy people shouldn't start taking the drug in the hopes of extending their own life spans -- at least not yet.

UW scientists Dr. Matt Kaeberlein, assistant professor of pathology, and Dr. Brian Kennedy, associate professor of biochemistry, study factors that control aging. They were asked by Nature to write a commentary on a paper published in the July 9 issue showing that dietary supplementation with rapamycin increases the life span of mice. They observed that, until recently, compounds that slow the hands of time were in the realm of science fiction, but with this finding may be closer to reality.

"The possibility that such compounds might exist, and might perhaps even be within reach," they wrote, "has gained scientific credibility."

Their News & Views editorial, "Ageing: A Mid-Life Longevity Drug?" noted that the study, co-led by Dr. David Harrison at the Jackson Laboratories in Maine, Dr. Richard Miller at the University of Michigan, and Dr. Randy Strong at the University of Texas Health Sciences Center at San Antonio, used a specially formulated, time-release rapamycin supplement in their laboratory mouse chow. Interestingly, the mice were not exposed to rapamycin in the diet until they were middle-aged, or, as the study reported, "roughly the equivalent of a 60-year-old person." Even so, the drug had a profound effect on lifespan.

Rapamycin was originally discovered in soil samples on Easter Island (Rapa Nui), famous for its towering, long-faced, stone Moai statues. Rapamycin already has a clinical role in reducing rejection of transplanted organs, in treating advanced kidney cancer, and in preventing narrowing of the heart's arteries after corrective surgery.

The study of rapamycin's longevity effects was part of the National Institute on Aging Interventions Testing Program. It accepts nominations for compounds from members of the scientific community, and selects the most promising to undergo parallel testing at three different institutions. Several compounds have been tested, but rapamycin is the first to significantly increase lifespan at all three centers in both male and female mice.

Rapamycin, which Kaeberlein, Kennedy and Dr. Stanley Fields, professor of genome sciences, had previously shown increases life span in yeast, is know to inhibit an enzyme called TOR. TOR activity is regulated by nutrient availability. Prior work by these UW scientists indicated that reducing TOR activity is central to how dietary restriction slows aging in yeast. Dietary restriction has long been known to slow aging in mice and to protect animals against age-related disorders like cancer, obesity, and heart disease. In the commentary, the authors suggest that the possibility that rapamycin is mimicking the effects of dietary restriction in mice merits further study.

The commentators also warn that healthy people shouldn't take rapamycin to slow aging because it can suppress the immune system. However, they don't rule out the possibility that rapamycin -- or more sophisticated interventions to reduce TOR activity -- might someday prove useful against age-related diseases. They also speculate that drug strategies might be discovered in the relatively near future to provide similar disease-fighting and longevity benefits without unwanted side effects.

The authors concluded: "Although extending human lifespan with a pill remains the purview of science fiction for now, the results of the study by Harrison and his colleagues provide reason for optimism that, even during middle age, there's still time to change the road you're on."

University of Washington

WHY WINNING ATHLETES ARE GETTING BIGGER

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While watching swimmers line up during the 2008 Olympic Games in Beijing, former Olympic swimmer and NBC Sports commentator Rowdy Gaines quipped that swimmers keep getting bigger, with the shortest one in the current race towering over the average spectator.

What may have been seen as an off-hand remark turns out to illustrate a trend in human development -- elite athletes are getting bigger and bigger.

What Gaines did not know was that a new theory by Duke University engineers has indeed showed that not only have Olympic swimmers and sprinters gotten bigger and faster over the past 100 years, but they have grown at a much faster rate than the normal population.

Futhermore, the researchers said, this pattern of growth can be predicted by the constructal theory, a Duke-inspired theory of design in nature that explains such diverse phenomena as river basin formation and the capillary structure of tree branches and roots. (http://www.constructal.com/).

In a new analysis, Jordan Charles, an engineering student who graduated this spring, collected the heights and weights of the fastest swimmers (100 meters) and sprinters (100 meters) for world record winners since 1900. He then correlated the size growth of these athletes with their winning times.

"The trends revealed by our analysis suggest that speed records will continue to be dominated by heavier and taller athletes," said Charles, who worked with senior author Adrian Bejan, engineering professor who came up with the constructal theory 13 years ago. The results of their analysis were published online in the Journal of Experimental Biology. "We believe that this is due to the constructal rules of animal locomotion and not the contemporary increase in the average size of humans."

Specifically, while the average human has gained about 1.9 inches in height since 1900, Charles' research showed that the fastest swimmers have grown 4.5 inches and the swiftest runners have grown 6.4 inches.

The theoretical rules of animal locomotion generally state that larger animals should move faster than smaller animals. In his contructal theory, Bejan linked all three forms of animal locomotion -- running, swimming and flying. Bejan argues that the three forms of locomotion involve two basic forces: lifting weight vertically and overcoming drag horizontally. Therefore, they can be described by the same mathematical formulas. (http://www.pratt.duke.edu/news/?id=1692)

Using these insights, the researchers can predict running speeds during the Greek or Roman empires, for example. In those days, obviously, time was not kept.

"In antiquity, body weights were roughly 70 percent less than they are today," Charles said. "Using our theory, a 100-meter dash that is won in 13 seconds would have taken about 14 seconds back then."

Charles, a varsity breaststroke swimmer during his time at Duke, said this new way of looking at locomotion and size validates a particular practice in swim training, though for a different reason. Swimmers are urged by their coaches to raise their body as far as they can out of the water with each stroke as a means of increasing their speed.

"It was thought that the swimmer would experience less friction drag in the air than in the water," Charles said. "However, when the body is higher above the water, it falls faster and more forward when it hits the water. The larger wave that occurs is faster and propels the body forward. A larger swimmer would get a heightened effect. Right advice, wrong reason."

In an almost whimsical corollary, the authors suggest that if athletes of all sizes are to compete in these kinds of events, weight classes might be needed.

"In the future, the fastest athletes can be predicted to be heavier and taller," Bejan said. "If the winners' podium is to include athletes of all sizes, then speed competitions might have to be divided into weight categories. Larger athletes lift, push and punch harder than smaller athletes, and this led to the establishment of weight classes in certain sports, like boxing, wrestling or weight-lifting.

(Photo: Duke University)

Duke University

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