FRIDAY - April 4, 2008------------------------------------------------------News Archive/Return to Today's News Alerts

Pregnant Mothers' Diet Linked to Baby's Obesity

Pregnant and lactating rats fed on a diet of hydrogenated fat during pregnancy and lactation had babies who were fatter than rats fed a normal diet, according to research published in Lipids in Health and Disease. The unhealthy diet has deleterious consequences even after the fats were removed from the diet and has links to insulin production.

“We know that foetal growth is influenced by the mother’s nutritional status,” explained Brazilian nutritionist Luciana Pisani. ”The nutritional conditions during pregnancy has a major role in the metabolic and hormonal interactions between the mother’s body, placenta and foetus. To date only a few studies have looked at the effects on trans fatty acids during pregnancy and lactation on the metabolism of offspring in adulthood. We found that the fatty content of the babies’ bodies increased when the mothers were fed the hydrogenated fat rich diet and this could be traced to the gene expression of adipokines.”

In an investigation to examine whether feeding pregnant and lactating rats hydrogenised fats rich in trans fatty acids, increased the fat content in carcass, the researchers found that their metabolic rate dropped dramatically. Interestingly young rats that were fed a normal diet after they were born ate less and weighed less even though their mothers had been eating the trans fatty acids while pregnant. The gene expression of adipokines was also examined in relation to insulin production.

The offspring were weighed weekly and exposure to the trans-fatty acid enriched diet after weaning led to a 40% increase in body fat content for the young rats. Rats whose mothers were fed the trans fatty acids and continued to eat the fats into adulthood had the highest metabolic efficiency. The same rats increased their insulin production.

Pisani continued, “Fats play a fundamental role in foetal development and changes in dietary fatty acids has important implications for foetal and postnatal development. Heavy ingestion of very hydrogenated fats rich in trans fatty acids increases risk of cardiovascular diseases and reduces insulin sensitivity and so leads to type 2 diabetes. We need to investigate this further as this has important implications for people’s own diets, especially pregnant women.”

Published April 4, 2008 by BioMed Central - Lipid World
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Stem Cell Breakthrough Offers Diabetes Hope

Scientists have discovered a new technique for turning embryonic stem cells into insulin-producing pancreatic tissue in what could prove a significant breakthrough in the quest to find new treatments for diabetes.

The University of Manchester team, working with colleagues at the University of Sheffield, were able to genetically manipulate the stem cells so that they produced an important protein known as a ‘transcription factor’.

Stem cells have the ability to become any type of cell, so scientists believe they may hold the key to treating a number of diseases including Alzheimer’s, Parkinson’s and diabetes.

However, a major stumbling block to developing new treatments has been the difficulty scientists have faced ensuring the stem cells turn into the type of cell required for any particular condition – in the case of diabetes, pancreatic cells.

“Unprompted, the majority of stem cells turn into simple nerve cells called neurons,” explained Dr Karen Cosgrove, who led the team in Manchester’s Faculty of Life Sciences. “Less than one per cent of embryonic stem cells would normally become insulin-producing pancreatic cells, so the challenge has been to find a way of producing much greater quantities of these cells.”

The pancreas contains different types of specialised cells – exocrine cells, which produce enzymes to aid digestion, and endocrine cells, including beta cells, which produce the hormone insulin to regulate the blood glucose levels. Diabetes results when there is not enough insulin to meet the body’s demands.

There are two forms of the disease: type-1 diabetes is due to not enough insulin being produced by the pancreas, while type-2 or adult-onset diabetes occurs when the body fails to respond properly to the insulin that is produced.

The team found that the transcription factor PAX4 encouraged high numbers of embryonic stem cells – about 20% – to become pancreatic beta cells with the potential to produce insulin when transplanted into the body. Furthermore, the scientists for the first time were able to separate the new beta cells from other types of cell produced using a technique called ‘fluorescent-activated cell sorting’ which uses a special dye to colour the pancreatic cells green.

“Research in the United States has shown that transplanting a mixture of differentiated cells and stem cells can cause cancer, so the ability to isolate the pancreatic cells in the lab is a major boost in our bid to develop a successful therapy,” said Dr Cosgrove. “Scientists have had some success increasing the number of pancreatic cells produced by altering the environment in which the stem cells develop, so the next stage of our research will be to combine both methods to see what proportions we can achieve.”

Scientists believe that transplanting functional beta cells into patients, most likely into their liver where there is a strong blood supply, offers the best hope for finding a cure for type-1 diabetes. It could also offer hope to those with type-2 diabetes whose condition requires insulin injections. But the more immediate benefit of the team’s research is likely to be in providing researchers with a ready-made supply of human pancreatic cells on which to study the disease process of diabetes and test new drugs.

The research, which was funded by the Juvenile Diabetes Research Foundation and the Medical Research Council, is published in the journal Public Library of Science (PLoS) One. Type-1 diabetes develops most frequently in children and adolescents; it is most commonly treated through regular injections of insulin into the bloodstream. Type-2 diabetes is much more common, accounting for about 90 per cent of all cases. It occurs most frequently in adults and is best controlled through careful regulation of sugar intake in the diet.

The pancreatic beta cells produced by the team resembled foetal pancreatic cells rather than the adult tissue. However, tests elsewhere on mice have shown these foetal cells are able to develop into adult cells following transplantation.Publication details: Liew CG, Shah NN, Briston SJ, Shepherd RM, Khoo CP, Dunne MJ, Moore HD, Cosgrove KE and Andrews PW (2008) Pax4 enhances beta-cell differentiation of human embryonic stem cells. PLoS One 3(3): e1783.

Published March 12, 2008 in the journal PLoS One
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Mitochondrial Mutations Make Tumors Spread

A new study published today in Science sheds light on how tumor metastasis occurs. It appears that mutations in mitochondrial DNA will initiate metastasis, but the possibility that it can be reversed with drugs exists, at least in mice.

Ten years ago, cancer researchers noticed that mitochondrial DNA (mtDNA - inherited from mothers) in tumor cells tends to be riddled with mutations - far more than normal. This is partly because mtDNA is not packaged in proteins, and thus more vulnerable to damage. Whether these mutations in mtDNA were the cause of cancer or a byproduct of cancer, was the question. However, people with mitochondrial diseases are not particularly cancer-prone, and cancer risk is not inherited maternally, as might be expected for a disease linked to mitochondria.

Jun-Ichi Hayashi's group at the University of Tsukuba in Japan and collaborators tested the two concepts of mtDNA damage by swapping two types of mouse tumor cells: one that tends to metastasize and another that does not. Injected under the skin of mice, the cells grew into tumors that eventually spread to the lungs. Mice receiving mtDNA from metastasizing cells had many more lung tumors than mice recieving less metastasis-prone cells, suggesting that mtDNA was the culprit. But, when mtDNA from metastatic cells was swapped with normal normal mtDNA in cells, it did not cause them to form tumors - so mtDNA does not seem to be involved in primary tumor formation on its own.

Metastatic mtDNA appeares to be the result of two mutations causing a deficiency in cellular respiratory activity and overproducing so-called reactive oxygen species (ROS) - molecules toxic to DNA. Yet when the researchers laced the drinking water of the mice that had metastatic cells placed under their skin, with ROS scavengers, the mice developed almost no lung tumors.

Hailing the experiment as "a technical tour de force," researcher Robert Taylor of Newcastle University in the U.K., says the fact that antioxidants suppressed metastasis warrants further study. However, Kornelia Polyak of the Dana-Farber Cancer Institute in Boston cautions that clinical trials testing antioxidants to prevent cancer have yielded mixed results in previous experiments and that giving antioxidants to someone on chemotherapy could interfere with the treatment.

Published April 3, 2008 in the journal Science
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THURSDAY - April 3, 2008--------------------------------------------------News Archive/Return to Today's News Alerts

Location of B12 Gene Mutations Corresponds to Disease Outcomes

The inability to break down vitamin B12 can lead to three devastating conditions: methylmalonic aciduria, homocystinuria, and a combination of the two, are the most frequent inborn errors caused by the inability to absorb vitamin B12. Although considered diseases of infancy, some patients develop symptoms in childhood, adolescence, or adulthood. Patients with the early-onset variety present within 12 months of age with severe neurologic, hematologic, and gastrointestinal abnormalities.

A new study now links them to mutations in different areas of the same gene. The finding could help solve the puzzle of how healthy people process this essential nutrient and how to design new treatment.

Vitamin B12 plays a critical role in nerve function, the production of red blood cells and DNA systhesis. People lacking a key protein for breaking down the B12 develop devastating health problems, including difficulty learning, psychosis, and anemia. Geneticist David Rosenblatt of McGill University in Montreal, Canada, began looking for the origin of the disorder in cells obtained from seven patients.

The responsible gene, dubbed MMADHC, appeared in people with any of the three conditions. In tests, normal copies of MMADHC delivered into the patients' cells restored those cells' ability to process vitamin B12.But It appears that the location of the mutations may explain the three conditions.

Patients with methylmalonic aciduria had mutations on one end of the gene, which resulted in a partial breakdown of vitamin B12 in addition to a buildup of byproducts. Patients with homocystinuria had mutations on the opposite end of the gene, that also allowed for partial processing of another B12 component, resulting in different byproducts building up that cause problems, the researchers say. Patients with both conditions simultaneously had mutations near the middle of the gene that caused an entirely dysfunctional protein triggering both disorders.

Charles Venditti, a biochemical geneticist at the National Human Genome Research Institute in Bethesda, Maryland, believes now that research has shown us where to look, screenings of newborns may detect even milder forms of the B12 disorder now unrecognized, that could lead to earlier intervention.

The sequence of the MMADHC gene is similar - but not identical - to the actions of a transporter gene used by certain bacteria to shuttle vitamin B12 around the cell. Rosenblatt speculates that the protein produced by the gene may be a novel transport system that human cells use to move vitamin B-12 into their mitochondria.

Published April 3, 2008 in the New England Journal of Medicine
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Motor Neuron Disease and Toxic Substances: Possible link?

Motor neuron disease is a rare, devastating illness which gradually deteriorates the nerve cells carrying signals back and forth from muscles to the brain.

One form of it, Lou Gehrig’s disease or ALS (amyotrophic lateral sclerosis), affects scientist Stephen J. Hawking. Writer Mitch Albom wrote “Tuesdays with Morrie” of Morrie Schwartz's declining years with ALS.

For most MND patients, the cause is never determined. Figuring out why the disease develops is an important step in possibly preventing it as well as develop therapies.

Now a team of University of Michigan scientists has gotten a step closer. They have discovered mutations in one key gene (neuropathy target esterase - NTE) that cause a previously unknown type of inherited motor neuron disease. Most intriguing, the scientists found the mutations caused changes in a protein already known to be involved in people who develop neurologic disorders as a result of exposure to toxic organophosphates - chemicals commonly used in solvents and insecticides and also as “nerve gas” agents.

“We speculate there may be gene-environment interactions that cause some forms of motor neuron disease,” says John K. Fink, M.D., professor of neurology at the U-M Medical School and senior author of the new study. He also is a researcher at the VA Ann Arbor Healthcare System. “Our findings support the possibility that toxic organophosphates contribute to motor neuron disease in genetically vulnerable people.” He believes the results suggest that altered activity of the gene found in patients in the study may also contribute to other motor neuron disorders, possibly including ALS. Fink examined members of two families who had progressive weakness and spasticity (tightness) in their legs, as well as muscle atrophy in their hands, shins and feet. Motor neuron disease affects five per 100,000 people.

“Why does one person in a family get it, and another doesn’t?”, the findings are an exciting first step in uncovering a possible link between the environment and motor neuron disease, says Shirley Rainier, a research assistant professor at the U-M Department of Neurology and the first author of the study. Rainier performed genetic studies and determined that the gene for the condition was on a region of chromosome 19.

In the 1930s, an estimated 50,000 people in the U.S. became lame or otherwise neurologically affected by neurotoxic organophosphates when they drank a contaminated batch of “ginger jake,” an alcohol-containing potion that was legal during Prohibition.

Ginger jake suppliers substituted a lubricating oil for the castor bean oil usually used in cooking after castor bean prices went up. A 2003 article in the New Yorker detailed the sad results, which led bands like the Mississippi Sheiks to write songs about the “ginger jake blues.”More r Recently there have been incidents in Fiji, India and Africa when accidental consumption of oils containing neurotoxic organophosphates (instead of cooking oil) caused death or nerve damage for tens of thousands of people. Although scientists don’t yet know the exact manner in which toxic organophosphate exposure leads to progressive and permanent nerve damage, they have learned that this process involves disturbance of an enzyme, NTE, contained within nerves.

Mark Leppert, Ph.D., co-chair of human genetics at the University of Utah, and his team performed genetic analysis confirming the location on the genome. Among the many genes in the region of chromosome 19, one stood out as particularly likely - it encodes for NTE - known for its role in organophosphate-induced neurological disease. It was studied immediately.

Analysis showed that neurologically affected people in each family had NTE gene mutations. These mutations altered the esterase domain - a critical part of the NTE protein. Fink has named the inherited condition “NTE motor neuron disease.” It begins in childhood and progresses slowly, with symptoms of weakness and spasticity in the legs and muscle atrophy in the hands and lower legs.

Next, Fink and his team want to learn if mutations in the NTE gene happen in other types of motor neuron disease such as ALS, and if the mutations make a person more vulnerable to neurological damage from organophosphate exposure.

Published March 3, 2008 in the American Journal of Human Genetics
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Proper Seatbelt Use by Pregnant Women Would Save 200 Fetuses a Year

A study, by researchers at the University of Michigan, found that about 200 fetuses each year would not be lost if pregnant women properly used their seatbelts every time they were in an automobile.

“It’s very clear, based on this study, that pregnant women should buckle up every single time they’re in a vehicle,” says senior author Mark D. Pearlman, M.D., vice-chair in the Department of Obstetrics and Gynecology at the U-M Health System. “Our study strongly suggests that about 200 fewer fetuses each year would die if women simply buckled up each time.” An estimated 370 fetuses die as a result of car crashes each year in the United States.

“Some women are very concerned because they think the lap belt will injure their unborn baby in a crash. This study shows that the opposite is true, that seatbelts clearly protect the fetus, in large part because the fetus protects the mother,” he notes. The study appears in the new issue of the American Journal of Obstetrics & Gynecology.

The study results have led Pearlman to initiate a campaign called Safe Babi (Seatbelts Are For Everyone – Buckle All Babies In).

Pearlman teamed up with researchers from the U-M Transportation Research Institute (UMTRI), the Department of Emergency Medicine and the College of Engineering to study data from 57 automobile crashes involving pregnant women. The study, the first of its kind, performed detailed crash analysis, including accurate estimates of the crash severity and direction, maternal restraint usage and pregnancy outcome.

Among six crashes involving improperly restrained women, three (50 percent) resulted in fetal death or major fetal complications. Among crashes involving 10 women who were not using seatbelts, eight (80 percent) of the crashes resulted in fetal death or major complications. These numbers compare with fetal death or serious complications in only 29 percent of crashes in which women were properly restrained by the seatbelt.

“Given that all cars in America have seatbelts, the potential benefits of these findings are significant,” says lead author Kathleen DeSantis Klinich, Ph.D., assistant research scientist with UMTRI. Some study results:

There are more fetal deaths due to car crashes than there are deaths of children due to bicycle accidents, or death of children due to car accidents in the first year of life.

The proper use of seatbelts by all pregnant women would prevent approximately 84 percent of serious adverse fetal outcomes (disabling injuries and deaths) due to car accidents.

If all women simply wore their seatbelts during pregnancy, ideally with the lap belt positioned under the pregnant abdomen, approximately 200 fetal lives would be saved (not including the prevention of an unknown number of pre-term births and placental abruptions which result in brain injury and other long-term disabilities.)

Pearlman encourages health care providers to remind all of their pregnant patients about the importance of using seatbelts (92% are much more likely to wear their seatbelts if the physician or nurse mentioned seatbelts versus 71% if they didn't).

Published April, 2008 in the European Journal of Human Genetics

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WEDNESDAY - April 2, 2008--------------------------------------------------News Archive/Return to Today's News Alerts

Feed A Cold!

Researchers studying deer mice have discovered evidence to support what mothers everywhere have long suspected: the immune system needs food to function properly.

In an article titled “Food Restriction Compromises Immune Memory in Deer Mice (Peromyscus maniculatus) By Reducing Spleen-Derived Antibody-Producing B-Cell Numbers,” Lynn Martin and coauthors find that reduced food intake leads to a decline in immune function in their subjects. The findings could have profound implications for human health.

Why immune activity is variable in many wild animals is a question that has long puzzled researchers. “Animals live different lifestyles, so they may use different types of defenses against infection depending on the situation. Perhaps this is why immune defenses vary seasonally in most species; some may be too expensive to use all the time,” Martin said, referring to previous work on Peromyscus and other small mammals and birds.

While it is known that the immune system expends energy when it gears up to fight a virus or an infection—a fever, for example—the researchers found that restricting their subjects’ diet by 30% significantly decreased the amount of available B cells, which produce antibodies and maintain immune memory. Without these cells, the immune system must relearn how to fight a threat if it reappears.

Research on the relationship between food and the immune system could have profound implications for humans. Martin and fellow researchers cite previous studies that have found that infections are “more frequent and tend to be chronic in malnourished children.” Vaccines, in order to work effectively, must provoke B cells to produce sufficient antibodies for immune memory. Previous studies have found that vaccines such as those for measles have a significantly lower rate of efficacy among the malnourished.

“A 30% restriction in food intake doesn’t affect body mass and only minimally reduces activity in deer mice, but it eliminates the long-term immune protection provided by antibodies. One wonders whether similar moderate food restriction has comparable immune effects in humans," Martin asked. Although other variables may be at work, the authors propose that for both wild animals and humans, food availability impinges on immunity and future research should determine what specific components of a diet (calories, protein, micronutrients) are responsible.

Published May - June, 2008 in the journal Physiological and Biochemical Zoology
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'Artificial Cell' Can Make Genes of Its Own

Resembling a computer chip and about as small as a stamp, an "artificial cell" that can synthesize genes and extract proteins from that gene, has been developed at Massachusetts Institute of Technology (MIT), in Boston, USA. Genes are vast libraries of information acting as resource material, while the proteins act as instructional manuals telling a cell what to do, i.e., how to use energy, identify attackers, divide into sister cells, and even die if necessary.

The new "artificial cell" offers a fast and cheap way to make "designer" proteins otherwise not found in nature - and might prove useful as a pretest site for evaluating an individual's reaction to drugs, before using the drugs on a patient.

The "cell" is made from layers of rubber, compressed into a solid surface that is then etched with a network of tiny passages and chambers. "This rubber has lines and features that are the size we need for our microfluidic chambers, channels and valves," says Peter Carr, who was also involved with the work. "With a few layers of this rubber, put together carefully, you can build a fairly complex device." Researchers have successfully integrated two "chips" into a single system already.The first

An "artificial cell" works through a series of heating and cooling cycles which control reactions. Next, a series of tiny pumps mix in enzymes to extract the needed proteins.First, a set of So far, the artificial cell has made a fluorescent protein from jellyfish. "We can see very clearly that we have functional glowing protein, so we know it works," says David Kong of MIT.

Kong believes his new device will be valuable for creating novel protein designs and is exploring ways to make much larger versions of the "artificial cell" - with thousands of reaction chambers - in order to synthesize many proteins at once. The cost of the protein design process, says Kong, is going to greatly affect the drug design process - hopefully driving down costs. "You can do 100,000 experiments for the price that people can normally do 50 experiments," he adds.

Carr has other hopes - that the "artificial cell" will be complex enough for use in cancer treatment. "I could start with the genetic information from a patient, program it into the device that we are working on, and essentially run a kind of simulation of how a drug might affect their cancer,” he explains.

Other groups have shown that proteins can be expressed in artificial conditions, but this new device has taken the idea of an artificial cell one step closer to reality, says Hugh Fan of the University of Florida, Gainesville, US, who was not involved in the study. "This group has advanced the field by showing the integration of gene synthesis with protein expression in one device,” Fan told New Scientist.

Presented March 27, 2008 at the Materials Research Society Spring Meeting
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Researchers Link 11 Genetic Variations to Type 2 Diabetes

Mathematicians at Michigan Technological University have developed powerful new tools for winnowing out the genes behind some of humanity’s most intractable diseases.

With one, they can cast back through generations to pinpoint the genes behind inherited illness. With another, they have isolated 11 variations within genes - called single nucleotide polymorphisms, SNPs or "snips" - associated with type 2 diabetes.

"With chronic, complex diseases like Parkinson's, diabetes and ALS [Lou Gehrig's disease], multiple genes are involved," said Qiuying Sha, an assistant professor of mathematical sciences. "You need a powerful test."

That test is the Ensemble Learning Approach (ELA), software that can detect a set of SNPs that jointly have a significant effect on a disease.

With complex inherited conditions, including type 2 diabetes, single genes may precipitate the disease on their own, while other genes cause disease when they act together. In the past, finding these gene-gene combinations has been especially unwieldy, because the calculations needed to match up suspect genes among the 500,000 or so in the human genome have been virtually impossible.

ELA sidesteps this problem, first by drastically narrowing the field of potentially dangerous genes, and second, by applying statistical methods to determine which SNPs act on their own and which act in combination. "We thought it was pretty cool," Sha said.

To test their model on real data, Sha’s team analyzed genes from over 1,000 people in the United Kingdom, half with type 2 diabetes and half without. They identified 11 SNPs that, singly or in pairs, are linked to the disease with a high degree of probability.

ELA is used to compare the genetic makeup of unrelated individuals to sort out disease-related genes. The team has also developed another approach, which uses a two-stage association test that incorporates founders' phenotypes, called TTFP, that can examine the genomes of family members going back generations.

"In the past, researchers have dealt with the nuclear family, parents and children, but this could go back to grandparents, great-grandparents . . . as far back as you want."

Published April, 2008 in the European Journal of Human Genetics
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TUESDAY - April 1, 2008----------------------------------------------------News Archive/Return to Today's News Alerts

Stem Cells from Hair Follicles May Help "Grow" New Blood Vessels

For a rich source of stem cells to be engineered into new blood vessels or skin tissue, clinicians may one day look no further than the hair on their patients' heads, according to new research published earlier this month by University at Buffalo engineers.

"Engineering blood vessels for bypass surgery, promoting the formation of new blood vessels or regenerating new skin tissue using stem cells obtained from the most accessible source -- hair follicles -- is a real possibility," said Stelios T. Andreadis, Ph.D., co-author of the paper in Cardiovascular Research and associate professor in the Department of Chemical and Biological Engineering in the UB School of Engineering and Applied Sciences.

Researchers from other institutions previously had shown that hair follicles contain stem cells.

In the current paper, the UB researchers demonstrate that stem cells isolated from sheep hair follicles contain the smooth muscle cells that grow new vasculature. The group recently produced data showing that stem cells from human hair follicles also differentiate into contractile smooth muscle cells.

"We have demonstrated that engineered blood vessels prepared with smooth muscle progenitor cells from hair follicles are capable of dilating and constricting, critical properties that make them ideal for engineering cardiovascular tissue regeneration," said Andreadis.

In addition to growing new skin for burn victims, cells from hair follicles could potentially be used to engineer vascular grafts and possibly regenerate cardiac tissues for patients with heart problems.

Since smooth muscle cells comprise the muscle of numerous tissues and organs, including the bladder, abdominal cavity and gastrointestinal and respiratory tracts, this new, accessible source of cells may make possible future treatments that allow for the regeneration of these damaged organs as well.

Andreadis and his colleagues previously engineered functional and implantable blood vessels with smooth muscle and endothelial cells originating from bone-marrow mesenchymal stem cells.

A key advantage of mesenchymal cells is that they typically do not trigger an immune reaction when transplanted, he said.

"Preliminary experiments in our laboratory suggest an exciting possibility -- that stem cells from hair follicles may be similar to bone-marrow mesenchymal cells," Andreadis said.

"The best case scenario is that from this one very accessible and highly proliferative source of stem cells, we will be able to obtain multiple different cell types that can be used for a broad range of applications in regenerative medicine," he said.

Published March 28, 2008 in the journal Cardiovascular Research
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Replacing Absent microRNAs Could Make Tumors Less Invasive, More Treatable

One group of small, non-coding RNA molecules could serve as a marker to improve cancer staging and may also be able to convert some advanced tumors to more treatable stages, report a University of Chicago-based research team in the April 1, 2008, issue of the journal Genes & Development.

Carcinomas are cancers that develop from epithelial tissue, which lines internal and external body surfaces. When normal cells are transformed into cancer cells, this epithelial tissue can take on the characteristics of embryonic tissue, known as mesenchymal tissue, which is comprised of unspecialized cells that will develop, as the embryo matures, into more specialized tissues.

That process also goes in reverse. Epithelial to mesenchymal transition (EMT) occurs, for example, during wound healing. In cancer, however, this process can produce invasive and mobile cells that can pass through membranes and travel to distant sites, where they seed new tumors.

"There are a bewildering numbers of pathways or stimuli that can either trigger EMT or reverse that process," said study author Marcus E. Peter, PhD, professor in the Ben May Department for Cancer Research at the University of Chicago. "What we have identified is a master regulator of EMT that is probably controlled by many of these stimuli."

Peter and colleagues showed that this master regulator consists of a specific group of microRNAs, a family called miR-200. MicroRNAs are tiny RNA molecules that have very important roles in gene regulation. They have multiple targets and act mainly by attaching themselves to specific sites in messenger RNA to prevent the production of proteins.

The authors studied a standard panel of 60 established human tumor cell lines representing nine different human cancers, as well as several specimens of human primary ovarian cancer. They showed that miR-200 was always present in epithelial (less invasive) and not in mesenchymal (more invasive) types of tumors.

"The importance of this finding is, first, that miR-200 may represent a good marker to stage cancer," Peter said, and "second, that reintroducing miR-200 into late cancer cells could provide a new form of treatment, preventing these cells from going through EMT and becoming more invasive."

Physicians already have a set of fairly reliable markers for carcinoma. Tumors with high levels of E-cadherin tend to be tightly tethered to nearby cells and less likely to break free and travel to other sites. Those with high Vimentin levels represent mesenchymal cells able to pass though other tissues.

Peter and colleagues found that miR-200 added mechanistic depth to those markers. Every tumor cell line the researchers tested that had the epithelial marker E-cadherin and not the mesenchymal marker Vimentin, had high amounts of miR-200. Every cell line with high Vimentin and no E-cadherin had no detectable miR-200.

"So we were able to show a complete correlation between miR-200 and E-cadherin/Vimentin expression," Peter added.

The authors found that miR-200 microRNAs helped regulate EMT transition. They bind directly to non-coding regions in the RNA of ZEB1 and ZEB2, known blockers of E-cadherin transcription. Both ZEB proteins have previously been implicated in human malignancies, ZEB1 in aggressive colorectal and uterine cancers, and ZEB2 in advanced stages of ovarian, gastric and pancreatic tumors.

By inhibiting miR-200, Peter and his coworkers could induce EMT. More important, by introducing miR-200, they managed to activate production of E-cadherin protein and reverse tumors from a more-invasive mesenchymal into a less-invasive epithelial form.

"In a previous paper we found that another micro RNA, let-7, drives tumor progression at an earlier stage," Peter said. "Let-7 appears to be a key player in preventing a cancer from becoming more aggressive. Now we want to figure out how these two micro RNAs work together to regulate carcinogenesis."

Once they understand this process, they want to use these microRNAs to treat cancer. Both microRNA families have the connection to drug resistance as well as to cancer stem cells, sub-population of cancer cells that have self-renewal properties and the ability to give rise to new tumors that are more resistant to current therapy.

"Our aim is not only to make tumors less invasive by reintroducing let-7 and miR-200," explained Peter. "We hope that we'll make tumors more sensitive to drugs and be able to target the stem cell population, which gives tumors their renewal capacity."

"The idea is a two-hit strategy," Peter said, "hit them first with the microRNA and make those drug-resistant cells sensitive again, then hit them again with low levels of conventional chemotherapy."

Published April 1, 2008 in the journal Genes & Development
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MRI Images of Genes in Action in the Living Brain

Biologists have just confirmed what poets have known for centuries: eyes really are windows of the soul - or at least of the brain. In a new study, Harvard researchers describe the development of gene probe eye drops that - for the first time - make it possible to monitor and detect tissue repair in the brain of living organisms using MRI. Current methods involve a risky, invasive, and relatively slow process of penetrating the skull to extract tissue samples and then examining those samples in a laboratory.

“We hope our study provides a tool for better treatments of neurological diseases, diagnosis, prognosis during therapy, and improved delivery of therapeutic agents to the brain,” said Philip Liu of Harvard, one of the researchers involved in the study. Liu also said that more research is necessary to determine exactly how these gene probes reach brain tissue.

In this report, Harvard researchers describe how they link a relatively common MRI probe (superparamagnetic iron oxide nanoparticles) to a short DNA sequence that binds to proteins in cells responsible for brain tissue repair (glia and astrocytes). Then, researchers used the eye drops on mice with conditions that cause “leaks” in the blood-brain barrier. When the animals’ brains were scanned using MRI, brain repair activity was visible. Glia and astrocytes help repair brain and nerve tissue, and have a role in numerous diseases and disorders that cause at least microscopic breaches in the blood-brain barrier, including traumatic brain injury, multiple sclerosis, stroke, cardiac arrest, and glioma, among others. Furthermore, the researchers believe that the probes may also help diagnose thinning of vascular walls in brains, which occurs as Alzheimer’s disease progresses.

“When people are sick, the last thing you want to do is puncture their skulls for a biopsy,” said Gerald Weissmann, MD, Editor-in-Chief of The FASEB Journal, “but sometimes this is unavoidable. These probes of genes in action go a long way toward ushering in an age where extracting brain tissue to identify a disease will seem as crude as when doctors measured skulls to diagnose a mental disease.”

Published April, 2008 in the journal The Federation of American Societies for Experimental Biology, FASEB
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MONDAY - March 31, 2008----------------------------------------------------News Archive/Return to Today's News Alerts

Breech Birth Linked to Gene Pattern

If one or both parents were born bottom first or feet first - called a breech delivery - their children are twice as likely to be born the same way, Norwegian researchers report.

Most babies are born head first, but about one in 20 is born bottom first. Breech deliveries increase the risk that the baby will die or suffer from health problems, the study authors noted.

"Both men and women delivered in breech presentation at term contribute to increased risk of breech delivery in their offspring," said lead researcher Tone Nordtveit, a research fellow at the University of Bergen. "Recurrence through the father is as strong as recurrence through the mother. Genes passed on from the father or the mother seem to be closely related to breech delivery," she added.

For the study, Nordtveit's team collected data on all births in Norway between 1967 in 2004. Specifically, they looked at information on first-born children.

"Men and women who themselves were delivered in breech presentation had more than twice the risk of breech delivery in their own first pregnancies compared with men and women who had been cephalic presentations," Nordtveit said.

When the researchers looked at 35,056 men who had children with two different women, they found the same risk for breech delivery, indicating that the increased risk appears to have a genetic component.

Predicting a breech delivery is important, Nordtveit said, because these deliveries are associated with increased mortality and morbidity.

"A considerable number of breech presentations are not detected before labor, despite careful antenatal surveillance," Nordtveit said. "To avoid undiagnosed breech deliveries, information about the mother's and the father's own presentation at birth will be valuable in the evaluation of fetal presentation in the third trimester."

Janet Hardy, an assistant professor of obstetrics/gynecology and pediatrics at the University of Massachusetts Medical School, agrees that knowing the parents' history of breech delivery may help predict the risk of their child having a breech presentation.

"Little is known about risk factors for breech presentation, and the idea that birth position might be inherited from either or both parents is novel," said Hardy, who authored an accompanying editorial in the journal.

"If these results hold true, further research may help us understand what trait is being passed from parent to child," she added. "Assessing the presence or absence of all potential risk factors for breech presentation, including the parents' own birth positions, may alert the clinician and patient to prepare for a possible breech delivery."

Published March 28, 2008 in the British Medical Journal
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Self-Assembled Materials Form Mini Stem Cell Lab

Imagine having one polymer and one small molecule that instantly assemble into a flexible but strong sac in which you can grow human stem cells, creating a sort of miniature laboratory. And that sac - if used for cell therapy - could cloak the stem cells from the human body’s immune system and biodegrade upon arriving at its destination, releasing the stem cells to do their work.

Futuristic? Only in part. A research team from Northwestern University’s Institute for BioNanotechnology in Medicine has created such sacs and demonstrated that human stem cells will grow in them. The researchers also report that the sacs can survive for weeks in culture and that their membranes are permeable to proteins. Proteins, even large ones, can travel freely across the membrane.

This new and unexpected mode of self-assembly, also can produce thin films whose size and shape can be tailored. The method holds promise for use in cell therapy and other biological applications as well as in the design of electronic devices by self-assembly, such as solar cells, and the design of new materials.

“We started with two molecules of interest, dissolved in water, and brought the two solutions together,” said Samuel I. Stupp, Board of Trustees Professor of Materials Science and Engineering, Chemistry and Medicine, who led the research.

“We expected them to mix, but, much to our surprise, they formed a solid membrane instantly on contact. This was an exciting discovery, and we then proceeded to investigate why it happened. Understanding the surprising molecular mechanism was even more exciting.”

One of the molecules is a peptide amphiphile (PA), small synthetic molecules that Stupp first developed seven years ago, which have been essential in his work on regenerative medicine. The other molecule is the biopolymer hyaluronic acid (HA), which is readily found in the human body, in places like joints and cartilage. Stupp recently had started a new research project on the regenerative medicine of cartilage, which drew him to hyaluronic acid.

“This is a clear example of informed discovery,” said Stupp, director of the Institute for BioNanotechnology in Medicine. “We knew there was something interesting about the interaction between peptide amphiphiles and biopolymers from our previous work on nanostructures that can cause blood vessels to grow. And we were particularly interested in hyaluronic acid because of its role in cartilage, a tissue that adults cannot regenerate and, when damaged in joints, causes grief to humans.”

Using just these two molecules, Stupp and his team can make many different structures, the two most important being sacs, which have a solid membrane on the outside and liquid inside, and flat membranes of any shape. The researchers can make the structures large or small, pick up the material with tweezers, stretch it and even easily repair the sacs through self-assembly should the material tear or have some other defect. The sacs also are robust enough to be sutured by surgeons to biological tissues.

The large (hyaluronic acid) and small (peptide amphiphile) molecules come together through supramolecular interactions, not by chemical reaction, in which covalent bonds are formed.

In the case of the flat membrane, the researchers put the peptide amphiphile solution at the bottom of a shallow mold and added on top the hyaluronic acid solution. The two interacted on contact, creating a solid. By varying the mold, the researchers produced a variety of shapes, including stars, triangles and hexagons, each having two chemically different surfaces. When dry, the materials are stiff and strong, like plastic.

In creating a sac, the researchers took advantage of the fact that hyaluronic acid (HA) molecules are larger and heavier than the smaller peptide amphiphile (PA) molecules. In a deep vial, they poured the PA solution and into that poured the HA solution. As the heavier molecules sank, the lighter molecules engulfed them, creating a closed sac with the HA solution trapped inside the membrane.

Having formed the sacs, Stupp and his team next studied human stem cells engulfed by the self-assembly process inside sacs that they placed in culture. The researchers found that the cells remained viable for up to four weeks, that a large protein -- a growth factor important in the signaling of stem cells -- could cross the membrane, and that the stem cells were able to differentiate.

“We expect that genes, siRNAs and antibodies will cross the membranes as well, making this mini cell biology lab a powerful device for research or therapies,” said Stupp. “For the development of cancer therapies, we will be able to confine cells within the sacs and study their reaction to different types of therapies as well as to signaling by different cells in neighboring sacs.”

In a clever demonstration of self-repair, if the sac’s membrane had a hole (from a needle injection, for example), the researchers simply placed a drop of the PA solution on the tear, which interacted with the HA inside, resulting in self-assembly and a sealed hole.

“The membrane is a fascinating and unusual structure with a high degree of hierarchical order,” said Stupp. “The membrane grows through a dynamic self-assembly process which generates hybrid nanofibers made up of both molecules and oriented perpendicular to the plane of the membrane. This architecture is very difficult to get spontaneously in materials. Using the right chemistry, the thick membrane structure could be designed to get conduits of charge in solar cells or nanoscale columns of catalytic nanostructures that would extend over arbitrary macroscopic dimensions.”

While the underlying, highly ordered structure of the sacs and membranes has dimensions on the nanoscale, the sacs and membranes themselves can be of any dimension and are visible to the naked eye.

Published March 28, 2008 in the journal Science
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Identical Genes From Parents May Raise Cancer Risk

People who have two identical copies of certain genes - one inherited from the mother and one from the father - seem to be at greater risk of developing a number of common types of cancer, research shows.

"This could represent a new way to do cancer risk-assessment. I suspect this will be added into routine clinical testing," said Dr. Charis Eng, senior author of the paper published in the March 26 issue of the Journal of the American Medical Association. "This is truly 'genetics to keep healthy people healthy,' " she said.

Unlike many currently available genetic tests - such as those for the BRCA1 and 2 genes thought to play a role in breast cancer - these anticipated tests could be applicable to everybody, not just people at high risk for a particular malignancy. Similarly, the new findings suggest that more than 5 percent of all cancers are linked to heredity, the researchers said.

Previously, Eng had noticed that a high level of germline cells (those containing genetic material that can be passed on to children) were homogenous, meaning that two copies of the same gene were identical. Her team was studying heterozygosity, but these cells were "maddeningly homogenous," she said. At first, she attributed the pattern to bad luck, but after years of finding the same thing, she decided it couldn't be a coincidence.

So, Eng and her colleagues decided to look at 400 genetic markers scattered throughout the genome in 385 breast, prostate and head and neck cancer patients and in people without cancer. All patients were of the same ethnic group.

"Lo and behold, in 16 markers, let's call them 'hot spots,' there were high frequencies of homozygosity compared to the controls," Eng said. The association was then validated in patients with lung cancer. This time, they streamed through 250,000 markers across the human genome and found that cancer patients were more likely to have homozygosity in the same 16 markers.

"We are saying that lack of genetic diversity or uniformity in hot spots in 16 places seems to be associated with common cancers," Eng said. "This is a novel means of cancer predisposition."

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