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Research Highlights

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Ivan Iossifov led a team of CSHL investigators in a study of 2500 families with a single child on the autism spectrum. Showing the power of quantitative biology when applied to human genetic datasets – in this case, the Simons Simplex Collection of families affected by autism – the team, which also included Mike Wigler, Dick McCombie, Dan Levy and Mike Schatz, provided the clearest view to date of the role of spontaneous mutations in autism. The team looked for de novo mutations—variations in genes occurring spontaneously in the affected child but not in the child’s parents or siblings. They tried to pinpoint which de novo mutations might be devastating ones, capable of causing autism spectrum disorder (ASD). They estimated that at least 30% of all ASD is caused by de novo mutations; they further estimated the total pool of spontaneously mutated genes contributing to ASD numbers around 400. Females, thought to have a protective factor against the impact of ASD-linked mutations, are more likely to have devastating, gene-disrupting mutations when they are symptomatic for ASD, the team suggested.

Bo Li and colleagues pinpointed where fear memories form in the mammalian brain. The team trained mice to be afraid of an auditory cue. They used a technique called optogenetics to activate specific neurons with colored laser light, directed fiberoptically into the brain with pinpoint accuracy. The team could then observe changes in behavior as different areas of the brain were optically stimulated. They found that fear conditioning alters the release of neurotransmitters in the central amygdala, an area associated with emotion, pain-processing and reward-based behavior. Experiments revealed that both the formation and recall of fear memory requires activation of somatostatin-positive neurons in the central amygdala. Such activation helps explain how the brain converts fear into behavior and indicates possible targets for new therapies for fear-related disorders such as acute anxiety and PTSD.

Clinical trials began for a drug to treat a fatal childhood disease, Spinal Muscular Atrophy (SMA).  The drug is the result of Adrian Krainer’s work on the mechanism-based design of antisense compounds that he found could correct splicing defects in target genes. The first such compound, ISIS-SMNRx, developed in close collaboration with Isis Pharmaceuticals, efficiently corrects defective splicing of SMN2 in preclinical models, and is now being tested in pediatric patients with spinal muscular atrophy (SMA), a severe motor-neuron disease for which no treatment currently exists. In March 2013, Isis reported positive data from a single-dose, open-label Phase 1 clinical study evaluating ISIS-SMNRx in children with SMA. Similar strategies may be applied for other splicing-related diseases. 
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Chris Vakoc used an unconventional approach to cancer drug discovery to identify a new potential treatment for acute myeloid leukemia (AML) which is being developed for therapeutic use for cancer patients by Tensha Therapeutics.  In collaboration with 5 other institutions, Vakoc pinpointed a protein called Brd4 as a novel drug target for AML, an aggressive blood cancer that is currently incurable in 70% of patients. Using a drug compound that inhibits the activity of Brd4, the scientists were able to suppress the disease in experimental models. This work represents an early success in CSHL's Cancer Therapeutics Initiative, which aims to rapidly identify new therapeutic targets and validate them in mouse models that closely mimic the behavior of specific human cancers. In addition to offering insights into cancers molecular mechanisms, this pre-clinical testing of drug candidates within a living animal allows researchers to evaluate cancer's response to new therapies and glean information that can be used to modify treatment strategies and increase the success rate of drugs that eventually enter the clinic.
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Zach Lippman and colleagues in Israel identify a single gene that dramatically boosts yield and sweetness in tomato hybrids.The yield-boosting power of this gene, which controls when plants make flowers, works in different varieties of tomato, and crucially, across a range of environmental conditions. The discovery has the potential to significantly change agricultural practices designed to get the most yield from flowering crops.
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Elizabeth Murchison, Gregory Hannon and colleagues discover a genetic marker for the facial cancer that is decimating Australia’s Tasmanian devil population.  The finding, which suggests that the cancers probably originated in Schwann cells, a type of tissue that cushions and protects nerve fibers, indicates new avenues for research into treatments and vaccines to save the endangered marsupials.
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A multi-institutional effort co-led by Doreen Ware, Richard McCombie and Robert Martienssen completes a reference genome for maize, one of the world’s most important crops.  The genome is a crucial starting point for scientists to understand the genetic differences between individual lines of maize and the function of every gene, especially those that affect important agricultural traits such as the ability to tolerate drought or dampness, size of seeds, etc.
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Scott Lowe’s laboratory develops new mouse models for human acute myeloid leukemia (AML) that accurately predict human response to chemotherapy.
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Yi Zhong identifies a protein that determines how long resting intervals between learning sessions need to last so that long-term memories can form.

A collaboration between five different research groups integrates genomic studies on human liver cancers with RNAi-based screening in a mouse model of the disease to identify 13 new tumor suppressor genes.

Adrian Krainer and colleagues induce cells to replenish a protein that, when deficient, leads to damage in growing nerve cells and muscles causing spinal muscular atrophy (SMA). These results hold out hope for one day successfully treating this often-fatal disease. 

Jonathan Sebat and Michael Wigler find a genetic distinction between sporadic and heritable forms of autism. 

Gregory Hannon, Scott Lowe, Robert Lucito, Scott Powers and Michael Wigler identify two genes on chromosome 11 that are likely to have a role in liver cancer. 

James Hicks shows that individual breast cancers can be diagnosed at the DNA level through a technique developed by Michael Wigler, which will allow physicians to make more accurate prognoses for patients. 

Richard McCombie and other CSHL scientists are part of an international team that deciphers the genome of humanity’s most important food source, rice. 

Gregory Hannon, Scott Lowe and Scott Powers discover microRNAs as new targets for improved diagnosis and treatment of lymphoma, colon cancer and other tumors. 

Leemor Joshua-Tor uncovers valuable clues for rational anti-malarial drug design and vaccine development by determining the structure of a protein that enables malaria parasites to invade red blood cells.

Michael Wigler and colleagues detect a surprising degree of large-scale variation in the copy number of genes in otherwise normal human genomes, by using a technique that they initially developed to detect differences between normal cells and cancer cells.

Gregory Hannon creates the first full-scale library of human RNAi clones. The library enables users in industry and academia to rapidly identify and validate target genes involved in a wide variety of diseases. 

Scott Lowe establishes a promising combination therapy for treating many cancers that do not respond to traditional chemotherapy. 

Timothy Tully and Joshua Dubnau identify a large group of candidate memory genes that are potential targets for the development of therapies for treating human memory disorders. 

Bruce Stillman discovers many important cellular proteins that duplicate chromosomal DNA before cell division. 

Edward Harlow and his colleagues establish a crucial functional link between the two general classes of cancer-causing genes (oncogenes and tumor-suppressor genes). 

Michael Wigler discovers the first cancer-causing gene in a human tumor. 

Joseph Sambrook, Phillip Sharp and William Sugden develop a technique for separating and visualizing DNA fragments that, even today, underpins all of molecular biology. 

Milislav Demerec greatly increases wartime penicillin production by isolating a high-yielding strain of the filamentous fungus Penicillium chrysogenum

George Shull forms the basis of modern agricultural genetics by crossing inbred lines of corn, thus discovering heterosis, or "hybrid vigor.

Carol Greider was named one of the first CSHL Fellows and continued her research on telomeres, which protect the greider_labends of chromosomes from degradation during cell division. She won the Nobel Prize in 2009 with Elizabeth Blackburn and Jack Szostak.

Within several years of his arrival at CSHL in 1972,richards sharp Richard Roberts and colleagues had discovered or characterized three-fourths of the world’s first restriction enzymes, proteins that could cleave DNA at specific sites. In the mid-1970s Roberts and Phillip Sharp, then also at CSHL, used these molecular scissors to probe the adenovirus genome. In 1977, Roberts, at CSHL, and Sharp, by this time at MIT, simultaneously discovered “split genes” – a phenomenon that led to the prediction of RNA splicing, the “editing” of RNA messages transcribed from DNA. For upending the long-held view that individual genes were continuous segments of DNA, the two were awarded the Nobel Prize in 1993.

James Watson gave the first public description of the newly discovered DNA double helix at the 1953 CSHL Symposium.watson_nobel The discovery influenced virtually all subsequent biological and medical research. Nine years later, Watson won the Nobel Prize with Francis Crick and Maurice Wilkins.

Experiments by Alfred
hershey_nobelHershey showed that DNA,not protein, is the genetic material of bacterial viruses. He won the Nobel Prize in 1969 for this and other work. 

Barbara McClintock discovered mobile genetic elements mcclintock_nobel
(“jumping genes”), a finding that has had profound importance for understanding chromosome structure and function. She won the Nobel Prize in 1983.

Beginning in 1941, Max Delbrück and Salvador Luria, both refugees of European fascism, began delbruck luriaspending summers at Cold Spring Harbor.  They pioneered the modern study of genetics in their investi-gations of tiny viruses called bacteriophages, or phages, which infect bacteria. Delbrück and Luria were the original protagonists of the historic Phage Group at Cold Spring Harbor, the intellectual center of a movement whose members launched the revolutionary field of molecular genetics. Delbrück himself taught the first edition of the legendary Phage course in 1945.  It influenced, among others, the 20-year-old James D. Watson, who attended in 1948.  Luria and Delbrück were awarded the Nobel Prize in 1969, along with Alfred Hershey, “for their discoveries concerning the replication mechanism and genetic structure of viruses.”