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Three Salk discoveries land on 2013 "best of the year" lists

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As 2013 came to a close, three Salk Institute discoveries won national recognition by being named to prestigious scientific "best of the year" lists. Science magazine lauded the groundbreaking work manipulating stem cells in Juan Carlos Izpisua Belmonte's lab, naming it a runner-up for 2013 Breakthrough of the Year. And team findings on the complexity of the human brain, research led by Fred "Rusty" Gage and Joe Ecker, earned the number four spot on a year-end list compiled by Tom Insel, director of the National Institute of Mental Health.

On a "ten best" list that included gene-editing, brain-imaging and sleep studies, the editors of Science praised researchers' success in getting pluripotent stem cells to grow into tiny "organoids" in the lab. "It's still a challenge to coax stem cells to grow into specific tissues, let alone into organized structures," the magazine's editors wrote. "This year, researchers did just that, in spectacular style, growing a variety of 'organoids' in the lab: liver buds, mini-kidneys, and, most remarkably, rudimentary human brains."

At the Salk Institute, Izpisua Belmonte and his team were able to grow the "mini-kidneys," an accomplishment reported earlier in Nature Cell Biology. Building on research that had indicated stem cells could be used to create precursors of kidney cells, the Salk team became the first to coax human stem cells into forming actual three-dimensional cellular structures similar to those found in human kidneys.

"Attempts to differentiate human stem cells into renal cells have had limited success," said Izpisua Belmonte, a professor in Salk's Gene Expression Laboratory and holder of the Roger Guillemin Chair. "We have developed a simple and efficient method that allows for the differentiation of human stem cells into well-organized 3D structures of the ureteric bud, which later develops into the collecting duct system."

In an initial testing of their protocol, Izpisua Belmonte' s team used induced pluripotent stem cells (iPSCs) collected from a patient with a genetic disorder known as polycystic kidney disease (PKD) and found that they were able to produce kidney structures from the patient-derived iPSCs. The team's accomplishment holds great promise for treating kidney disease, since these organs rarely recover function once they are damaged. For the year-end list compiled by NIH's Tom Insel, Salk scientists Fred Gage and Joe Ecker were lauded for their work revealing new complexities in the human brain in two separate papers published in Science.

"2013 will be the year when we begin to realize how much the brain differs from other organs," Insel wrote. "We already knew that cells in the brain express (translate into protein) more of the genome and use more energy than any other organ. But two discoveries this year really made the case for the human brain as not only the most mysterious but the most exceptional of organs."

One discovery came from the lab of Fred Gage, professor in the Laboratory of Genetics and holder of the Vi and John Adler Chair for Research on Age-Related Neurodegenerative Disease. Using single-cell sequencing, Gage and his colleagues showed that the genomic structures of individual neurons differ from each other even more than expected. The scientists took a high-level view of the entire genome, looking for large deletions and duplications of DNA called copy number variations (CNVs). What they discovered was that as many as 41 percent of the cells in the frontal cortex have at least one mutation, with a million DNA bases either duplicated or deleted.

"These are mutations not seen in blood cells (which are the basis for all psychiatric genetic studies)," Insel wrote, "or in neurons elsewhere in the brain."

A discovery by Joe Ecker, professor and director of Salk's Genomic Analysis Laboratory and holder of the Salk International Council Chair in Genetics, added to the unfolding appreciation of the brain's complexity. When the discovery was first published, NIH director Francis Collins described it as revealing "an entirely new perspective on a fundamental issue in biology or medicine."

Working with Salk professor Terry Sejnowski, holder of Salk's Francis Crick Chair, Ecker and his team showed that the landscape of DNA methylation, a particular type of epigenomic modification, is highly dynamic in brain cells during the transition from birth to adulthood, helping to understand how information in the genomes of cells in the brain is controlled from fetal development to adulthood.

"The entire DNA strand consists of only four bases: cytosine, guanine, adenine and thymine," Insel wrote in his year-end roundup. "Whereas in most cells in the body silencing occurs where cytosine and guanine are adjacent, brain cells follow a different set of rules with all the base pairs involved. This means that the mechanisms by which experience influence biology are completely different in brain cells compared to blood cells or liver cells."

Underscoring the value of the research performed by the two Salk teams, Insel concluded, "The lesson is that we cannot use peripheral cells to know what is happening in the brain."