September 13, 2008, Stanford University Medical Center — Marauding molecules cause the tissue damage that underlies heart attacks, sunburn, Alzheimer’s and hangovers. But scientists at the Stanford University School of Medicine say they may have found ways to combat the carnage after discovering an important cog in the body’s molecular detoxification machinery.

The culprit molecules are oxygen byproducts called free radicals. These highly unstable molecules start chain reactions of cellular damage – an escalating storm that ravages healthy tissue.

“We’ve found a totally new pathway for reducing the damage caused by free radicals, such as the damage that happens during a heart attack,” said Daria Mochly-Rosen, PhD, professor of chemical and systems biology and the senior author of a study reporting the new findings. The research will appear in the Sept. 12 issue of Science.

Before the study, scientists knew that heart muscle could be preconditioned to resist heart attack damage – for instance, moderate drinkers tend to have smaller, less severe heart attacks than teetotalers. But scientists didn’t understand how pre-conditioning worked.

To figure out how alcohol protects heart muscle from free-radical damage, Mochly-Rosen’s team tested alcohol pretreatment in a rat heart-attack model. They compared the enzymes activated during the attacks to those switched on with no alcohol. Enzymes are the “doers” of the cellular machinery, catalyzing all of the biochemical reactions that form the basis of life.

Surprisingly, the treatment activated aldehyde dehydrogenase 2 (ALDH2), an obscure alcohol-processing enzyme. Alcohol pretreatment increased the enzyme’s activity during heart attack by 20 percent, leading to a 27 percent drop in the associated damage.

“Although this enzyme was discovered a long time ago, my research group knew nothing about the enzyme except that it helps remove alcohol when people drink,” said Mochly-Rosen, who is also the senior associate dean for research in the School of Medicine and the George D. Smith Professor in Translational Medicine.

ALDH2 wasn’t one of the well-studied antioxidant players that the scientists expected to find fighting free-radical damage. The enzyme neutralizes an aldehyde molecule, a toxic byproduct of the ethanol in alcoholic beverages. But aldehydes are also formed in the body when free radicals react with fat molecules.

The body’s cells contain a lot of fat, Mochly-Rosen noted. “It’s very easy for free radicals to find fat and oxidize it to aldehydes.”

Inside cells, the accumulating aldehydes permanently bind and damage cellular machinery and DNA. Such damage occurs in many diseases, from heart attack and Parkinson’s to sun-induced aging of the skin.

After learning of ALDH2’s novel role in reducing the damage, the researchers searched for a molecule that could make the enzyme function even better. They enlisted the Stanford High Throughput Bioscience Center, directed by David Solow-Cordero, PhD, to find a molecule that heightened the enzyme’s activity.

The winner of this contest was a tiny molecule that reduced heart attack damage by 60 percent in the rat model. The molecule, Alda-1, has a surprising mode of action: it protects ALDH2 itself from aldehyde attack. The enzyme, it turns out, was being hobbled by the very chemical it removes.

Because Alda-1 is small, it should be easy to adapt for pharmacological use, Mochly-Rosen said. She expects the new molecule to have many possible drug applications.

“It has a huge potential use,” she said. So far, Alda-1 has been tested only in the rat model, but Mochly-Rosen’s lab is investigating other possible applications, such as fighting neurodegenerative disease and sun damage on the skin. The team also hopes to interest drug companies in human trials.

In addition to its lofty medical applications, Alda-1 could also have a much lowlier use: fighting hangovers. Many nasty hangover symptoms are due to aldehyde buildup.

The tiny molecule may also improve alcohol tolerance and reduce susceptibility to free-radical diseases in people with a common ALDH2 mutation. The mutation affects 40 percent of people of Asian descent and causes an intolerance for alcohol.

Mochly-Rosen’s Stanford team included Che-Hong Chen, PhD, a senior scientist and a key contributor; postdoctoral scholars Grant Budas, PhD, and Eric Churchill, PhD; and senior scientist Marie-Helene Disatnik, PhD. Thomas Hurley of the University of Indiana School of Medicine collaborated with the Stanford scientists.

The research was funded by the National Institute on Alcohol Abuse and Alcoholism and also received support from Stanford’s SPARK program, which helps mature nascent medical technologies with the goal of transferring them to commercial entities to benefit society.

September 12, 2008, UT Southwestern Medical Center — A bacterial molecule that initially signals to animals that they have been invaded must be wiped out by a special enzyme before an infected animal can regain full health, researchers at UT Southwestern Medical Center have found.

Using a genetically engineered mouse model, the team found that simply eradicating the infection-causing bug isn’t enough to restore an animal’s immune function. Lipopolysaccharide, or LPS, the dominant bacterial “signal” molecule that heralds the invasion, must also be inactivated. The findings are to appear online Sept. 11 in Cell Host & Microbe.

“We think this is the first evidence that killing the causative agent of a bacterial infection isn’t enough for an animal to recover fully,” said Dr. Robert Munford, professor of internal medicine and microbiology, and senior author of the study. “You’ve got to get rid of this molecule that the host is responding to or else its immune system remains suppressed.”

By sensing and responding to LPS, animals mobilize their defenses to attack and kill the bacteria. This immune response also causes inflammation in the host. For a few days after the infection begins, however, an animal’s ability to sense the bacteria is turned down, presumably to prevent further inflammation. In the current study, the researchers found that mice didn’t recover from this “tolerant” period unless the LPS was inactivated by acyloxyacyl hydrolase, an enzyme discovered in 1983 by Dr. Munford and Dr. Catherine Hall, now an assistant professor of internal medicine at UT Southwestern.

Dr. Mingfang Lu, instructor of internal medicine and lead author of the current study, said the team also found that prolonged tolerance was immunosuppressive, reducing the animal’s ability to stave off another bacterial infection.

Dr. Lu said that how long an animal remains in this tolerant state varies from animal to animal. “But mice that can’t make the enzyme acyloxyacyl hydrolase seem to stay tolerant forever, leaving them unable to fight additional infections,” she said.

For the study, researchers injected LPS or a common bacterium that makes LPS into the abdomens of two types of mice: ones that could produce the acyloxyacyl hydrolase enzyme and ones that could not. Two weeks later they injected the mice with a deadly strain of Escherichia coli – which can cause loss of water and salts, damage to blood vessels, and bleeding in humans – to gauge how prolonged tolerance influences the animal’s internal defense mechanisms.

Though almost all of the mice with the enzyme survived, 90 percent of those without the enzyme died. “Being tolerant, or unable to respond normally, made them more susceptible to the E coli we injected them with,” Dr. Lu said.

Dr. Munford said they don’t have any evidence that this finding is applicable to humans, who also make the enzyme, but it is possible.

“One theory is that there is variability among humans in the production of acyloxyacyl hydrolase,” he said. “We don’t know this yet, but if it’s true, then the presence or absence of the enzyme might contribute to the length of immunosuppression after serious bacterial infections. It might even be reversible if we could provide the enzyme or figure out a way for people to make more of it.”

The team’s next step is to investigate further how LPS continues to stimulate the host’s immune cells for such long periods of time if it does not get degraded. They also hope to use this animal model to understand better on a molecular scale exactly what happens during post-infection immunosuppression.

Other UT Southwestern researchers involved in the study were Dr. Alan Varley, assistant professor of internal medicine, and John Hardwick, former research associate in internal medicine. Shoichiro Ohta, a researcher from Saga Medical School in Japan, also contributed to the study.

The work was supported by the National Institute of Allergy and Infectious Diseases.

9284F0AD-DEFB-4B0E-BC20-524F57F37415.jpg
A diabetic patient injects himself (abdomen) with insulin at the J.W.C.H. safety-net clinic in downtown Los Angeles
July 30, 2007. REUTERS/Lucy Nicholson

ScienceDaily.com. Harvard Medical School — Researchers have transformed ordinary cells into insulin-producing cells in a living mouse, improving symptoms of diabetes in a major step towards regenerative medicine.

The technique, called direct reprogramming, bypasses the need for stem cells — the body’s master cells which, until now, have been indispensable to efforts to custom-make tissue and organ transplants.

The researchers used three genes carried by an ordinary virus to transform mouse exocrine cells, which make up about 95 percent of the pancreas, into the scarce insulin-producing beta cells that are destroyed in type 1 or juvenile diabetes.

In theory, the same is possible using abundant human cells such as liver, skin or fat cells, Dr. Douglas Melton and colleagues at Harvard Medical School and Children’s Hospital in Boston reported.

“It was easier than one might have thought,” Melton, a Howard Hughes Medical Institute researcher and one of the world’s top stem cell experts, said in a telephone interview.

“These cells are very stable and live for the life of the mouse.”

Scientists had been counting on stem cells to show them how to regenerate tissues and organs — in the case of juvenile diabetes, to regenerate the pancreatic cells that are mistakenly destroyed by the body’s immune system.

“I wake up every day thinking about how to make beta cells,” said Melton, whose two children have type 1 diabetes.

The most malleable and promising stem cells have been embryonic stem cells, taken from days-old embryos. But U.S. federal law strictly limits funding for such research and they are not easy to create.

CELL REPROGRAMMING

Last year, researchers discovered how to reprogram ordinary skin cells by taking them back to an embryonic-like state. These induced pluripotent stem cells can be used to study disease and might one day make tailor-made transplants.

But now Melton and his team — using knowledge gained from these earlier studies — have skipped both steps.

“What this shows is that you can go directly from one type of adult cell to another, without going back to the beginning,” said Melton.

Reporting in the journal Nature, the team said they did it in living mice, not in lab dishes.

They worked with diabetic mice that do not have the insulin-producing cells needed by the pancreas to help the body turn food into energy.

Melton’s team had to find which genes were needed to make cells function as the precious beta-cells. While every cell carries the full genetic code, only certain genes in any cell are working at any given time.

The researchers had to find out which genes are “on” as an embryo grows its pancreas.

Out of more than 1,000 genes, they found just three were needed — Ngn3, Pdx1, and Mafa. Then an ordinary cold virus called an adenovirus carried these three genes into the digestive-juice-making exocrine cells of the pancreas.

This converted about 20 percent of the exocrine cells to beta cells that produced insulin, in turn lowering the soaring blood sugar levels in the mice.

The method might work first in people with severe type 2 diabetes, whose bodies no longer make insulin, Melton said.

“For type 1 diabetes we are still faced with the annoying problem of autoimmune attack,” he said.

Any transformed cells in type 1 diabetes would be destroyed by the same mistaken immune response that caused the disease in the first place.

Before experiments begin in people, Melton wants to find a way to transform cells without using a virus. Using viruses to treat people, he noted, is risky and makes Food and Drug Administration experts nervous.

September 12, 2008, Indiana University (Cognitive Sci) — New research from Indiana University has found evidence that how we look for things, such as our car keys or umbrella, could be related to how we search for more abstract needs, such as words in memory or solutions to problems.

“Common underlying search mechanisms may exist that drive our behavior in many different domains,” said IU cognitive scientist Peter Todd. “If how people search in space is similar to how they search in their minds, it’s a very exciting prospect to try to find the deep, underlying roots of human behavior that may be common to varied domains.”

Lead author Thomas Hills worked with Todd and fellow IU cognitive scientist Robert Goldstone in designing experiments to explore the search processes their study participants used in both spatial and abstract settings. The studies revolved around two search modes — exploitation, where seekers stay with a place or task until they have gotten appreciable benefit from it, and exploration, where seekers move quickly from one place or one task to another, looking for a new set of resources to exploit. They then examined whether an initial search, in this case for resources in space, primed the mode used in the subsequent, more abstract search.

“We asked the question — are the same mechanisms that let simpler organisms search in space for food related to how we search for things in our mind, for concepts or ideas,” Todd said. “Our conclusion is that they seem to be linked at some level, which is what our priming experiment suggests.”

Some people might be more inclined to one search mode or the other, having a lesser ability to focus on a given task or difficulty letting go of an idea. An extreme form of the exploratory cognitive style would be someone with attention deficit hyperactivity disorder. An extreme form of the exploitive cognitive style would be someone with obsessive compulsive disorder.

These new findings, published in the latest issue of “Psychological Science,” have possible implications related to other recent work on brain chemistry and cognitive disorders. Exploratory foraging — actual or abstract — appears to be linked to decreases in the brain chemical dopamine. Many problems related to attention — including ADHD, drug addiction, some forms of autism and schizophrenia — have been linked to such a dopamine deficit. The authors suggest that computer foraging, such as that used for their experiments, could reveal individual differences in underlying cognitive search style, and could even be used to manipulate that style. If that were possible, it could perhaps lead to therapies for such cognitive disorders.

Modern tools — a computerized search game and board game — used to examine ancient cognitive search processes

The scientists had a group of volunteers use icons to “forage” in a computerized world, moving around until they stumbled upon a hidden supply of resources (akin to food or water), then deciding if and when to move on, and in which direction. The scientists tracked their movements.

The volunteers explored two very different worlds. Some foraged in a “clumpy” world, which had fewer but richer supplies of resources. Others explored a “diffuse” environment, which had many more, but much smaller, supplies. The idea was to “prime” the optimal foraging strategy for each world. Those in a diffuse world would in theory do better giving up on any one spot quickly and moving on, and navigating to avoid any retracing. Those in a clumpy world would do better to stay put in one area for an extended period, exploiting the rich lodes of resources before returning to the exploratory mode.

The volunteers then participated in a more abstract, intellectual search task — a computerized game akin to Scrabble. They received a set of letters and had to search their memory for as many words as they could make with those letters. As with the board game, they could also choose to trade in all their letters for a new set whenever they wanted to.

The researchers found that the human brain appears capable of using exploration or exploitation search modes depending on the demands of the task, but it also has a tendency through “priming” to continue searching in the same way even if in a different domain, such as when switching from a spatial to an abstract task.

They also found that individuals were consistent in their cognitive style — the most persevering foragers for resources in space were also the most persevering Scrabble players. Everybody should be able to switch back and forth, Todd said, but the people who have a tendency to use one mode more in one task have a similar tendency to use that mode more in other tasks.

Journal reference:

1. Thomas T. Hills, Peter M. Todd, and Robert L. Goldstone. Search in External and Internal Spaces: Evidence for Generalized Cognitive Search Processes. Psychological Science, 2008; 19 (8): 802 DOI: 10.1111/j.1467-9280.2008.02160.x

Scientists race to crack the potato’s genetic code

By Tarry Wade, ScienceDaily.com — Scientists around the world have teamed up to sequence the genome of the potato, hoping to crack the genetic code of one of the world’s most important crops at a time of surging population growth and high food prices.

Solanum tuberosum, the scientific name of the humble white potato, looks simple. But it is chock full of mysteries hidden in its 12 chromosomes and 840 million DNA base pairs. Humans, by comparison, have 3 billion DNA base pairs.

The Potato Genome Sequencing Consortium includes scientists in 13 countries from New Zealand to India and Peru who are decoding different pieces of the genome.

It plans to have its work done in 2010 and will then make its findings public so plant breeders can create new seeds resistant to everything from droughts and diseases to extreme temperatures.

“We’ll be able to design seeds more effectively and more efficiently after we know precisely which genes do what,” said Gisella Orjeda, a biology professor at the Cayetano Heredia University in Lima who runs a lab that is sequencing one of the chromosomes.

Once the white potato genome is sequenced, researchers say it will become easier to identify genes in native and wild species of potatoes, which come in 5,000 varieties.

The potato, the world’s third-most important food crop after wheat and rice, is being championed by food security experts who say it could cheaply feed an increasingly hungry world.

The United Nations named 2008 the International Year of the Potato to highlight its potential as an antidote to hunger.

Though the potato originated 8,000 years ago in Peru’s Andes mountains, China is now the largest grower of the tuber. More farmers are planting it, especially in developing countries, as the world’s population expands by 1 billion a decade.

Orjeda said the potato genome sequencing project, centered in the Netherlands (www.potatogenome.net), could usher in a new era for the potato, which its proponents call history’s most important vegetable.

“The potato isn’t just important now. It has always been important — it’s what enabled the Industrial Revolution in Europe (by allowing for a population boom), but also what caused the potato famine in Ireland,” she said.