Will Jonathan Sebat Warn That Older Paternal Age is a Robust Cause of Schizophrenia and Autism

ONLINE EDITION FRIDAY December 26, 2008



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Cold Spring Harbor Laboratory's
10 Leading Research Discoveries of 2008
In 2008, scientists at Cold Spring Harbor Laboratory (CSHL) published dozens of research articles in the most prestigious journals of their respective fields. Their accomplishments stretched from discovering important new information about the genetic underpinnings of devastating diseases including schizophrenia and cancer, to piecing together the signaling networks and molecular mechanisms put into play by disease-related genes.

Research teams at the Laboratory also discovered the far-reaching power of various small RNA molecules to regulate genes and protect the genome; worked out "epigenetic" mechanisms of inheritance in various organisms; and descended into the mysterious depths of the brain to chart the structural and mechanistic basis of information processing.

The achievements described here are "only a sample of the literally dozens of path breaking studies that our faculty completed through early December," notes CSHL President Bruce Stillman, Ph.D. Stillman points out that CSHL is at the very top of a short list of research institutions judged by independent analysts at Thomson Reuters to have had the most profound impact upon the field of molecular biology in the period since 2003, the year in which the full reference version of the human genome was published. "Being at the leading edge in such an intensely competitive field is a significant achievement, especially for an institution of our size," Stillman added.

CSHL: 10 Research Highlights for 2008
Role of rare gene mutations in schizophrenia.

Jonathan Sebat and colleagues from the University of Washington and the NIMH added a solid clue to the biological puzzle of schizophrenia. The team identified multiple, individually rare gene mutations in people with schizophrenia that may help explain how the illness is caused. Screening the genome for either deletions or duplications -- what are called gene copy-number variations, or CNVs -- they found that deletions, disruptions and duplications of normal genes were three to four times more frequent in people with schizophrenia than in healthy controls. Moreover, they found more than half of the mutations disrupted genes in pathways implicated in neuronal development and regulation.

A rapid new screening approach identifies 13 tumor suppressor genes in liver cancer.

Building on technologies to identify cancer "hotspots" in the genome, tools to precisely recreate these genetic errors in normal cells, and mouse models to test for the emergence of cancer, five CSHL teams led by Scott Lowe and Scott Powers devised a powerful new screening approach. In contrast to other strategies that take years to test the validity of each gene or mutation in causing cancer, the rapid new screen has the added advantage of only revealing genes that make a functional contribution to the disease process. In a first test, the pay-off was the identification of 13 previously unidentified tumor suppressors - genes that protect against cancer. Such genes are of great interest, in part because they're often missing in samples of tissue taken from liver cancer patients.

Senescence can protect liver tissue against cirrhosis, acute tissue damage.

When cells enter a senescent or "quiet" state, they don't actively divide. Scott Lowe and his team have studied senescence in the context of liver cancer: the activation of senescence in mouse tumor cells, they found, caused liver tumors to shrink by drawing in immune killer cells that destroyed the newly senescent cells. In 2008 the Lowe lab discovered a role for senescence in non-cancer pathology such as that seen in liver cirrhosis and other forms of acute liver damage. Studies in mice showed that senescent cells located in damaged areas of the liver tissue called fibroses provoke a beneficial immune reaction that limits fibrotic lesions and curtails tissue injury.

Splicing together a new therapeutic strategy for a devastating spinal disorder.

In spinal muscular atrophy (SMA), a devastating neuromuscular disease, severe damage to nerve cells and connected muscles stems from a protein deficiency. Adrian Krainer and his team have identified the genetic misstep that results in this deficiency - an error in a common process known as alternative splicing that results in the production of an incomplete RNA molecule that, when normal, serves as a template for making the essential protein. Krainer has designed synthetic molecules that help generate the correct RNA, and is now testing whether his strategy will redress the protein anomaly in SMA patients, a possible strategy for reversing the disease.

Cellular 'compasses' keep breast cells off the highway to cancer.

Studying proteins that position cells in the right location and direction within tissues, a team led by Senthil Muthuswamy formulated a new paradigm for thinking about how breast cancer originates and progresses. They showed that one of these cellular "compasses," a protein called Scribble, goads breast epithelial cells into forming the correct duct-like structures and resisting cancer formation. When Scribble stops functioning, the tissues lose shape and cancer ensues, as the team observed in scores of breast cancers from patients.

A molecular scaffold that supports nerve networks in the developing brain cells or "neurons" are organized into complex networks in which they communicate with each other by flashing signals across junctions called synapses. Josh Huang and his team discovered that neurons connect to very specific partners at very specific spots thanks to an underlying framework of molecular "guides" called glial cells. These cells don't send signals, but instead nudge nerve fibers to grow in the right direction and make the right contacts. Huang hopes that piecing together such details on how the brain is wired will help clarify what goes wrong in disorders such as autism.

Re-thinking the thought process.

What's the smallest time interval that you need to decide between a chai and a latte at Starbucks? Well, if you were a rat and the choices were given to you as two different electrical pulses, you'd be able to make a decision even if the two pulses were only 3 milliseconds apart. This remarkable insight comes from the recent work of Anthony Zador and his team, who studied a process known as "spike timing" - the ability of neurons to fire electrochemical pulses or "spikes" in sync with cues they receive from other neurons. Their data supports a novel, alternative theory of how information is processed in the brain. Also in 2008, Adam Kepecs and colleagues demonstrated that rats make calculations about confidence as part of their decision-making process. They suggest that estimation of confidence may be the product of a very basic kind of information processing in the brain, shared widely across species and not strictly confined to humans and other primates.

Deeper insights about RNAs, large and small.

CSHL researchers are contributing to a growing body of evidence debunking the idea that the most of the human genome - some 98 percent of it - is genetic "junk." A team in David Spector's lab shed light in 2008 on possible functions of "non-coding" RNA molecules, announcing the discovery of a previously unknown mechanism in the nucleus that sends different parts of a non-coding RNA molecule called MALAT1 to different cellular destinations. Gregory Hannon and his team found that many seemingly non-functional genes (called "pseudogenes") are a source of small regulatory RNA-molecules that can activate the cell's regulatory apparatus and modify gene activity. His team also identified a new class of small RNAs which, unlike previously discovered small RNAs, both modifies gene activity and acts as an innate defense mechanism against genome-damaging parasites called transposons.

RNA interference helps "silent" DNA remain quiet.

About a tenth of our DNA is silent -- wound into tightly packed clumps called heterochromatin, which unwinds to replicate only when the cell itself divides -- and then reverts to "packed" form in daughter cells. Robert Martienssen and his team found that this inherited clumping of DNA, which causes genes to be expressed in distinctive ways, is transmitted across generations due to a phenomenon called RNA interference (RNAi). They found that during replication, the previously "silent" heterochromatic DNA was copied into small RNA molecules, which in turn guided clumping proteins back to the DNA that they originated from, thereby re-silencing that DNA.

Sequencing of platypus genome unlocks evolution's secrets.

The platypus seems to have had a long, drawn out identity crisis: it is an egg-laying mammal with many confounding physical features. And for scientists, it represents the perfect candidate to understand how genomic innovations and changes are instigated by evolution. In 2008, CSHL scientists were part of a consortium that sequenced the platypus genome. In addition to cataloguing the unique and bizarre features of the genome (10 sex chromosomes!), CSHL's Gregory Hannon and his team separately studied classes of small RNAs present in the platypus, highlighting roles for various types both unique and "conserved" across species by evolution.

For more information, visit www.cshl.edu.