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RETT SYNDROME RESEARCH TRUST

Kelly Rae Chi

[links to podcasts are below]

That mutations in the MECP2 gene cause Rett Syndrome has been known for over a decade. But what exactly the protein does is not yet clear.

In the early 90s, Adrian Bird’s group purified MeCP2—which stands for methyl-CpG binding protein 2—and named the protein for its ability to bind parts of the DNA with a chemical tag called a methyl. Methyls tend to dampen the expression of genes, suggesting that MeCP2’s function is to silence genes.

Studies published since then suggest MeCP2 activates or represses the expression of many genes. Other results suggest that the protein binds throughout the genome, influencing the way DNA packs into a cell.

New evidence, published today (December 21) in Cell, shows that MeCP2 binds to spots throughout the genome that are tagged with the chemical, 5-hydroxymethylcytosine (5hmC) in mice, and that this interaction may be important for understanding Rett Syndrome.

“[The study is] a very interesting new development in studying the functional significance of MeCP2, which we have to understand if we’re going to understand Rett Syndrome,” says Bird, professor of genetics at the University of Edinburgh in Scotland who was not involved with work.

Abundant in the DNA of certain brain cells, 5hmC seems to be a signpost of sorts for active spots within the genome — that is, the regions that are churning out new protein — the study found. MeCP2’s latching onto these sites supports its potential role as a gene activator, though it’s clear that the case of what MeCP2 does is far from closed.

“Whether or not [MeCP2 is] directly involved in activation is still a matter of further investigation. But we know that it can localize to a region that contains 5hmC and active genes,” says Skirmantas Kriaucionis, group head in the University of Oxford Nuffield Department of Medicine, who co-led the study with Nathaniel Heintz of the Rockefeller University in New York.

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heintz-skiri

Podcast with Skirmantas Kriaucionis

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Figuring out 5hmC

As a postdoctoral researcher in Heintz’s lab, Kriaucionis found 5hmC in 2009 by accident when he was looking at how a closely related chemical, 5-methylcytosine (5mC), influences genome structure in brain cells. Anjana Rao’s group, then at Harvard Medical School, working independently from Heintz’s lab, confirmed the existence of 5hmC in the same issue of the journal.

Researchers consider 5mC a fifth base, and 5hmC a sixth base, of DNA, which is traditionally thought of as a string of four different chemicals called nucleotides. 5mC and 5hmC resemble the traditional base cytosine, but with a methyl group added on, making 5mC, and a hydroxy group added to the methyl, creating 5hmC. The new study confirmed that patterns of these chemical modifications to the genome are different in each cell and influence which genes are turned on or off and when.

The discovery of 5hmC opened up a new area of work—and hundreds of new papers—focused on where the nucleotide is in the genomes of different cell types, and what it’s doing.

In the new study, using an explorative molecular assay to fish for a binding partner for 5hmC, the group identified the molecule as MeCP2, and nothing else. “It was really a surprise,” Kriaucionis says.

“This paper is the second paper to suggest a candidate binding protein for 5hmC,” says Rao, now a professor of signaling and gene expression research at the La Jolla Institute for Allergy and Immunology, who was not involved with the new study. Other findings have proposed a different molecule, MBD3, as a candidate, but those and the new results need further investigation, she adds.

“So far, both candidates — MBD3 and MeCP2—also bind 5mC, so an exclusive binding protein for 5hmC has not yet emerged,” Rao says.

Indeed, contradicting the new evidence that MeCP2 binds 5hmC and 5mC equally, some previous studies show that MeCP2 much prefers binding to 5mC over 5hmC. For example, a study published earlier this year shows that says MeCP2 is nearly 20 times more likely to bind 5mC than 5hmC.

Relating to Rett

In the new study, Kriaucionis and his colleagues observed that a certain Rett-causing mutation, called R133C—which is responsible for a relatively milder form of the disorder—disrupts MeCP2’s binding to 5hmC.

“[The R133C mutation] is really interesting because it allows us to speculate that MeCP2 binding to 5hmC is important as a part of the function which causes Rett Syndrome,” Kriaucionis says.

The evidence now “strongly suggests” the potential involvement of 5hmC in Rett, says Peng Jin, an associate professor of human genetics who was not involved with the new study. A study his group published last year in Nature Neuroscience found that patterns of 5hmC are altered in mouse models of Rett.

Interestingly, the R133C mutation only slightly dampens MeCP2’s interaction with 5mC, suggesting that MeCP2’s binding with 5mC serves a different purpose than that of MeCP2 and 5hmC.

Other Rett-causing mutations in MeCP2 examined by the group don’t seem to affect binding to 5hmC, meaning 5hmC binding does not fully explain the symptoms of Rett.  “It will be important to test further the contribution of 5hmC to Rett Syndrome,” notes Jin, adding that there are mouse models available to do so. Those mutant mice lack the enzymes needed to convert 5mC to 5hmC.

In the new study, researchers studied only a few types of neurons, but there are hundreds of cell types in the brain. Kriaucionis thinks that MeCP2 binds to 5hmC in other cells.

The 5hmC patterns themselves are cell-specific, however, perhaps further complicating the story of MeCP2.

“We really need to get more data to understand whether or not, how different 5hmC and MeCP2 localization would be in different cell types,” Kriaucionis says. “It’s an important component to understand MeCP2 function,” and how scientists might think about future treatment.

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Cell podcast with Nat Heintz    (click on Paperclick on right)

HHMI Press Release

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RETT SYNDROME RESEARCH TRUST

The current issue of Businesweek includes an interesting article on the challenges of drug discovery.  The quote from Margaret Anderson really resonates “The challenge in medical research is that there ultimately is no one in charge.”  In one simple sentence she gets to the root of why RSRT and other disease specific non-profits exist:  someone needs to be in charge!

Illustration by 731; Pills: Dwight Eschliman/Getty Images  |  One out of every 5,000 to 10,000 potential treatments discovered in the lab makes it to market.

Illustration by 731; Pills: Dwight Eschliman/Getty Images | One out of every 5,000 to 10,000 potential treatments discovered in the lab makes it to market.

Speeding Up the Discovery of Drugs

By on November 29, 2012  |  Businessweek

When Scott Johnson read an article about a potential breakthrough that restored nerve function in mice with multiple sclerosis, he assumed it would soon be turned into a treatment. That was in 2001. Johnson, who was diagnosed with MS at age 20 in 1976, is still waiting.

A Silicon Valley entrepreneur who has led startups in areas as diverse as food processing and simulated helicopter flights, Johnson founded the Myelin Repair Foundation in 2002 with the goal of halving the time it takes to develop new MS treatments. Now he’s part of a growing movement to fix the messy, uncoordinated way new medicines are created. “I realized that it was literally a totally dysfunctional system,” says Johnson. “It’s not surprising no drugs come out.”

The distance between a scientific discovery and a commercial treatment is known in the drug industry as the “valley of death,” and that’s where most medical innovations end up. For every 5,000 to 10,000 potential treatments discovered in the lab, only one makes it to market, according to the Pharmaceutical Research and Manufacturers of America (PhRMA), the drug industry lobby. And while total spending on research and development by the industry and the National Institutes of Health has increased from about $50.3 billion in 2001 to $80.4 billion in 2011, according to PhRMA data, the number of new drugs approved each year has remained roughly constant at 20 to 30.

“The challenge in medical research is that there ultimately is no one in charge,” says Margaret Anderson, executive director of FasterCures, a Washington nonprofit trying to speed up medical breakthroughs. “It’s not like building the atomic bomb or mapping the genome, those big scientific projects where there was one goal everybody’s trying to get to.”

(CONTINUE READING ON THE BUSINESSWEEK WEBSITE)

RETT SYNDROME RESEARCH TRUST WEBSITE

This week’s issue of Nature contains a provocative article (see below)  suggesting that the National Institutes of Health is missing the mark by funding “safe” science rather than novel and potentially game-changing research.  The claim is hardly new.  In fact scientists often joke that in order to get NIH funding one needs to have already completed the experiments and have data in hand.  The Nature article now backs up the charge with data of its own –  the majority of the nation’s most influential scientists are not receiving NIH funding.  Why this is happening may be easy to explain. How to fix it is likely to be problematic.

While this issue will be the topic of ongoing discussions for months and years to come at NIH, Congress and academic institutions around the country one thing is starkly clear: there is a great need for organizations like RSRT that do not shy away from high-risk projects.

nature

“Capecchi got the grant and put all the money into the part the reviewers discouraged. “If nothing happened, I’d be sweeping floors now,” he said. Instead, he discovered how to disable specific genes in animals and shared the 2007 Nobel Prize for medicine for it.”

“Conformity,” “mediocrity” win biomedical funding, say critics
By Sharon Begley for Reuters

NEW YORK (Reuters) – Accusations that the leading U.S. funders of biomedical research “ignore truly innovative thinkers” and “encourage conformity if not mediocrity” are seldom heard in the polite precincts of top science journals. Yet they are front and center in a paper published Wednesday in the journal Nature, which concludes that fewer than half of America’s most influential and productive biomedical scientists now receive funding from the National Institutes of Health.

Critics have long argued that NIH, which spends some $30 billion a year on biomedical research at universities and medical centers worldwide, funds conventional, incremental science rather than swing-for-the-fences studies more likely to produce breakthroughs. But the new analysis goes further: It marshals data to show that U.S. biomedical researchers who make the most influential discoveries are not getting NIH support.

“I was astonished” by the findings,” said Jack Dixon, vice president and chief scientific officer of the nonprofit Howard Hughes Medical Institute (HHMI), who was not involved in the study. “It’s just amazing that most of NIH’s $30 billion is going to scientists who haven’t had the greatest impact.” (continue reading on Reuters.com)