‘Junk DNA’ drives embryonic development

Contact: Heather Buschman, Ph.D. hbuschman@sanfordburnham.org 858-795-5343 Sanford-Burnham Medical Research Institute

Sanford-Burnham researchers discover that microRNAs play an important role in germ layer formation—the process that determines which cells become which organs during embryonic development

             IMAGE:   These are differentiating mouse embryonic stem cells (green = mesoderm progenitor cells, red = endoderm progenitor cells). The microRNAs identified in this study block endoderm formation, while enhancing mesoderm formation.Click here for more information.

LA JOLLA, Calif., December 3, 2012 – An embryo is an amazing thing. From just one initial cell, an entire living, breathing body emerges, full of working cells and organs. It comes as no surprise that embryonic development is a very carefully orchestrated process—everything has to fall into the right place at the right time. Developmental and cell biologists study this very thing, unraveling the molecular cues that determine how we become human.

“One of the first, and arguably most important, steps in development is the allocation of cells into three germ layers—ectoderm, mesoderm, and endoderm—that give rise to all tissues and organs in the body,” explains Mark Mercola, Ph.D., professor and director of Sanford-Burnham’s Muscle Development and Regeneration Program in the Sanford Children’s Health Research Center.

In a study published in the journal Genes & Development, Mercola and his team, including postdoctoral researcher Alexandre Colas, Ph.D., and Wesley McKeithan, discovered that microRNAs play an important role in this cell- and germ layer-directing process during development.

MicroRNA: one man’s junk is another’s treasure

MicroRNAs are small pieces of genetic material similar to the messenger RNA that carries protein-encoding recipes from a cell’s genome out to the protein-building machinery in the cytoplasm.  Only microRNAs don’t encode proteins. So, for many years, scientists dismissed the regions of the genome that encode these small, non-protein coding RNAs as “junk.”

We now know that microRNAs are far from junk. They may not encode their own proteins, but they do bind messenger RNA, preventing their encoded proteins from being constructed. In this way, microRNAs play important roles in determining which proteins are produced (or not produced) at a given time.

MicroRNAs are increasingly recognized as an important part of both normal cellular function and the development of human disease.

So, why not embryonic development, too?

Directing cellular traffic

To pinpoint which—if any—microRNAs influence germ layer formation in early embryonic development, Mercola and his team individually studied most (about 900) of the microRNAs from the human genome. They tested each microRNA’s ability to direct formation of mesoderm and endoderm from embryonic stem cells. In doing so, they discovered that two microRNA families—called let-7 and miR-18—block endoderm formation, while enhancing mesoderm and ectoderm formation.

The researchers confirmed their finding by artificially blocking let-7 function and checking to see what happened. That move dramatically altered embryonic cell fate, diverting would-be mesoderm and ectoderm into endoderm and underscoring the microRNA’s crucial role in development.

             IMAGE:   Mark Mercola, Ph.D., is a professor and program director at Sanford-Burnham Medical Research Institute.Click here for more information.

But they still wanted to know more…how do let-7 and miR-18 work? Mercola’s team went on to determine that these microRNAs direct mesoderm and ectoderm formation by dampening the TGFβ signaling pathway. TGFβ is a molecule that influences many cellular behaviors, including proliferation and differentiation. When these microRNAs tinker with TGFβ activity, they send cells on a certain course—some go on to become bone, others brain.

“We’ve now shown that microRNAs are powerful regulators of embryonic cell fate,” Mercola says. “But our study also demonstrates that screening techniques, combined with systems biology, provide a paradigm for whole-genome screening and its use in identifying molecular signals that control complex biological processes.”

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This research was funded by the California Institute for Regenerative Medicine, the U.S. National Institutes of Health (National Heart, Lung, and Blood Institute grants R33 HL088266 and R01 HL113601), and the American Heart Association.

Original paper:

Colas AR, McKeithan WL, Cunningham TJ, Bushway PJ, Garmire LX, Duester G, Subramaniam S, & Mercola M (2012). Whole-genome microRNA screening identifies let-7 and mir-18 as regulators of germ layer formation during early embryogenesis. Genes & development PMID: 23152446

About Sanford-Burnham Medical Research Institute

Sanford-Burnham Medical Research Institute is dedicated to discovering the fundamental molecular causes of disease and devising the innovative therapies of tomorrow. The Institute consistently ranks among the top five organizations worldwide for its scientific impact in the fields of biology and biochemistry (defined by citations per publication) and currently ranks third in the nation in NIH funding among all laboratory-based research institutes. Sanford-Burnham utilizes a unique, collaborative approach to medical research and has established major research programs in cancer, neurodegeneration, diabetes, and infectious, inflammatory, and childhood diseases. The Institute is especially known for its world-class capabilities in stem cell research and drug discovery technologies. Sanford-Burnham is a U.S.-based, non-profit public benefit corporation, with operations in San Diego (La Jolla), California and Orlando (Lake Nona), Florida. For more information, news, and events, please visit us at sanfordburnham.org.

Compound found in rosemary protects against macular degeneration in laboratory model

Contact: Heather Buschman, Ph.D. hbuschman@sanfordburnham.org 858-795-5343 Sanford-Burnham Medical Research Institute

Sanford-Burnham researchers discover that carnosic acid, a component of the herb rosemary, promotes eye health in rodents—providing a possible new approach for treating conditions such as age-related macular degeneration

      IMAGE:   Left: This shows control cells exposed to hydrogen peroxide. Right: This shows cells treated with carnosic acid are protected from hydrogen peroxide. Live cells are stained green, dead cells are…Click here for more information.

 

LA JOLLA, Calif., November 27, 2012 – Herbs widely used throughout history in Asian and early European cultures have received renewed attention by Western medicine in recent years. Scientists are now isolating the active compounds in many medicinal herbs and documenting their antioxidant and anti-inflammatory activities. In a study published in the journal Investigative Ophthalmology & Visual Science, Stuart A. Lipton, M.D., Ph.D. and colleagues at Sanford-Burnham Medical Research Institute (Sanford-Burnham) report that carnosic acid, a component of the herb rosemary, promotes eye health.

Lipton’s team found that carnosic acid protects retinas from degeneration and toxicity in cell culture and in rodent models of light-induced retinal damage. Their findings suggest that carnosic acid may have clinical applications for diseases affecting the outer retina, including age-related macular degeneration, the most common eye disease in the U.S.

Age-related macular degeneration

Age-related macular degeneration likely has many underlying causes. Yet previous studies suggest that the disease might be slowed or improved by chemicals that fight free radicals—reactive compounds related to oxygen and nitrogen that damage membranes and other cell processes.

Lipton’s team first discovered a few years ago that carnosic acid fights off free radical damage in the brain. In their latest study, Lipton and colleagues, including Tayebeh Rezaie, Ph.D. and Takumi Satoh, Ph.D., initially investigated carnosic acid’s protective mechanism in laboratory cultures of retinal cells.

The researchers exposed the cells growing in the dish to hydrogen peroxide in order to induce oxidative stress, a factor thought to contribute to disease progression in eye conditions such as macular degeneration and retinitis pigmentosa. They found that cells treated with carnosic acid triggered antioxidant enzyme production in the cells, which in turn lowered levels of reactive oxygen and nitrogen species (cell-damaging free radicals and peroxides).

Rosemary’s therapeutic potential

Lipton, Rezaie, Satoh and colleagues next tested carnosic acid in an animal model of light-induced damage to photoreceptors—the part of the eye that converts light to electrical signals, enabling visual perception. As compared to the untreated group, rodents pre-treated with carnosic acid retained a thicker outer nuclear layer in the eye, indicating that their photoreceptors were protected. The carnosic acid-treated rodents also exhibited better electroretinogram activity, a measure of healthy photoreceptor function.

What’s next for carnosic acid? “We’re now developing improved derivatives of carnosic acid and related compounds to protect the retina and other brain areas from a number of degenerative conditions, including age-related macular degeneration and various forms of dementia,” said Lipton, director of Sanford-Burnham’s Del E. Webb Neuroscience, Aging, and Stem Cell Research Center and an active clinical neurologist.

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Note to members of the media: Please contact Heather Buschman at hbuschman@sanfordburnham.org to schedule on-site, phone, or Skype interviews with Stuart A. Lipton, M.D., Ph.D. Images are also available upon request.

This research was funded by the U.S. National Institutes of Health: Eunice Kennedy Shriver National Institute of Child Health & Human Development grant P01 HD29587; National Institute of Environmental Health Sciences grant P01 ES016738; National Institute of Neurological Disorders and Stroke grant P30 NS076411; National Eye Institute grant R01 EY05477

The study was co-authored by Tayebeh Rezaie, Sanford-Burnham; Scott R. McKercher, Sanford-Burnham; Kunio Kosaka, Nagase & Co., Ltd.; Masaaki Seki, Sanford-Burnham; Larry Wheeler, Allergan, Inc.; Veena Viswanath, Allergan, Inc.; Teresa Chun, Allergan, Inc.; Rabina Joshi, Sanford-Burnham; Marcos Valencia, Sanford-Burnham; Shunsuke Sasaki, Iwate University; Terumasa Tozawa, Iwate University; Takumi Satoh, Sanford-Burnham and Iwate University; and Stuart A. Lipton, Sanford-Burnham.

About Sanford-Burnham Medical Research Institute

Sanford-Burnham Medical Research Institute is dedicated to discovering the fundamental molecular causes of disease and devising the innovative therapies of tomorrow. The Institute consistently ranks among the top five organizations worldwide for its scientific impact in the fields of biology and biochemistry (defined by citations per publication) and currently ranks third in the nation in NIH funding among all laboratory-based research institutes. Sanford-Burnham utilizes a unique, collaborative approach to medical research and has established major research programs in cancer, neurodegeneration, diabetes, and infectious, inflammatory, and childhood diseases. The Institute is especially known for its world-class capabilities in stem cell research and drug discovery technologies. Sanford-Burnham is a U.S.-based, non-profit public benefit corporation, with operations in San Diego (La Jolla), California and Orlando (Lake Nona), Florida. For more information, news, and events, please visit us at sanfordburnham.org.

How antipsychotic medications cause metabolic side effects such as obesity and diabetes

LA JOLLA, Calif. — In 2008, roughly 14.3 million Americans were taking antipsychotics—typically prescribed for bipolar disorder, schizophrenia, or a number of other behavioral disorders—making them among the most prescribed drugs in the U.S. Almost all of these medications are known to cause the metabolic side effects of obesity and diabetes, leaving patients with a difficult choice between improving their mental health and damaging their physical health. In a paper published January 31 in the journal Molecular Psychiatry, researchers at Sanford-Burnham Medical Research Institute (Sanford-Burnham) reveal how antipsychotic drugs interfere with normal metabolism by activating a protein called SMAD3, an important part of the transforming growth factor beta (TGFbeta) pathway.

The TGFbeta pathway is a cellular mechanism that regulates many biological processes, including cell growth, inflammation, and insulin signaling. In this study, all antipsychotics that cause metabolic side effects activated SMAD3, while antipsychotics free from these side effects did not. What’s more, SMAD3 activation by antipsychotics was completely independent from their neurological effects, raising the possibility that antipsychotics could be designed that retain beneficial therapeutic effects in the brain, but lack the negative metabolic side effects.

“We now believe that many antipsychotics cause obesity and diabetes because they trigger the TGFbeta pathway. Of all the drugs we tested, the only two that didn’t activate the pathway were the ones that are known not to cause metabolic side effects,” said Fred Levine, M.D., Ph.D., director of the Sanford Children’s Health Research Center at Sanford-Burnham and senior author of the study.

In a previous study aimed at developing new insights into diabetes, Dr. Levine and his team used Sanford-Burnham’s high-throughput screening capabilities to search a collection of known drugs for those that alter the body’s ability to generate insulin, the pancreatic hormone that helps regulate glucose. That’s when they first noticed that many antipsychotics alter the activity of the insulin gene. In this current study, the researchers set out to connect the dots between antipsychotics and insulin. In doing so, experiments in laboratory cell-lines showed that antipsychotics known to cause metabolic side effects also activated the TGFbeta pathway—a mechanism that controls many cellular functions, including the production of insulin—while the drugs without these side effects did not.

Wondering whether their initial laboratory observations were relevant to the human experience, the researchers reanalyzed previously published gene expression patterns in brain tissue from schizophrenic patients treated with antipsychotics. What they found supported their earlier findings—TGFbeta signaling was activated only in those patients receiving antipsychotic treatment. Looking further, they found that the extent to which each antipsychotic drug activated the TGFbeta pathway in human brains correlated very closely with the extent to which those same drugs activated SMAD3 and affected the insulin promoter in their cell culture experiments.

The TGFbeta pathway also plays an important role in metabolic disease in people who don’t take antipsychotic medications. “It’s known that people who have elevated TGFbeta levels are more prone to diabetes. So having a dysregulated TGFbeta pathway—whether caused by antipsychotics or through some other mechanism—is clearly a very bad thing,” said Dr. Levine. “The fact that antipsychotics activate this pathway should be a big concern to pharmaceutical companies. We hope this new information will lead to the development of improved drugs.”

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This study was funded by a gift from Mr. T. Denny Sanford to the Sanford Children’s Health Research Center at Sanford-Burnham. Co-authors include Thomas Cohen, Sanford-Burnham and University of California, San Diego; S. Sundaresh, NextBio; and Fred Levine, Sanford-Burnham.

About Sanford-Burnham Medical Research Institute

Sanford-Burnham Medical Research Institute is dedicated to discovering the fundamental molecular causes of disease and devising the innovative therapies of tomorrow. The Institute consistently ranks among the top five organizations worldwide for its scientific impact in the fields of biology and biochemistry (defined by citations per publication) and currently ranks third in the nation in NIH funding among all laboratory-based research institutes. Sanford-Burnham is a highly innovative organization, currently ranking second nationally among all organizations in capital efficiency of generating patents, defined by the number of patents issued per grant dollars awarded, according to government statistics.

Sanford-Burnham utilizes a unique, collaborative approach to medical research and has established major research programs in cancer, neurodegeneration, diabetes, and infectious, inflammatory, and childhood diseases. The Institute is especially known for its world-class capabilities in stem cell research and drug discovery technologies. Sanford-Burnham is a U.S.-based, non-profit public benefit corporation, with operations in San Diego (La Jolla), Santa Barbara, and Orlando (Lake Nona). For more information, please visit our website (http://www.sanfordburnham.org) or blog (http://beaker.sanfordburnham.org). You can also receive updates by following us on Facebook and Twitter.