Salk Institute Research Articles

AAA award winners

AAA award winners

RNA de-inhibition

Small RNAs are famous for their gene-silencing ability. But new results from Tomoko Kuwabara, Fred H. Gage (Salk Institute, La Jolla, CA), and colleagues show that some tiny RNA species turn genes on, not off. Figure NRSE dsRNA (red) makes NRSF/REST (green) an activator in differentiating neurons. This new class of RNAs is needed to make neurons. “Small double-stranded RNAs exist in reasonably high concentrations in cells that have just committed to neuronal lineages,” says Gage. These RNAs are homologous to a promoter sequence called NRSE/RE-1, which is found in a wide range of genes that are expressed only in neurons. In other cell types, these genes are known to be shut off by the NRSF/REST repressor. The group shows that this repressor becomes an activator when NRSE dsRNAs are around. As a result, neuronal genes are turned on, and multipotent adult neural stem cells become neurons. The NRSF/REST protein binds strongly to the dsRNA, and the two probably sit on promoters as a complex. When both are present, histone acetylases and chromatin-remodeling proteins replace the deacetylases and methyl-DNA binding proteins that are found at neuronal gene promoters when only NRSF is expressed. The dsRNAs are found in regions of the hippocampus where neurons are differentiating, and their destruction prevents cultured cells from becoming neurons in response to inducing signals. A single molecule RNA switch that creates an entire lineage may not, however, be found outside neurons. “It's an unusual case,” says Gage, “because of NRSF. It binds to so many promoters that it makes the RNAs generalizable.” ▪ Reference: Kuwabara, T., et al. 2004. Cell. 116:779–793. [PubMed]

Jobs

Roots. Salk Institute professor Juan Carlos Izpisúa Belmonte is a wanted man in his native land. The Spanish health minister and Catalonian officials want the 42-year-old Belmonte to return home to lead a new national bank of embryonic stem cells scheduled to open in 2005 in Catalonia's capital, Barcelona.

Corticorelin: ACTH RF, corticoliberin, corticotrophin-releasing hormone, corticotropin-releasing factor, human corticotropin-releasing hormone, ovine corticotrophin-releasing factor, Xerecept.

Neurobiological Technologies in the US is clinically developing corticorelin [ACTH RF, corticoliberin, corticotrophin-releasing hormone, corticotropin-releasing factor, human corticotropin-releasing hormone; Xerecept], a synthetic preparation of the peptide hormone Corticotropin-Releasing Factor (CRF), as a potential treatment for the reduction of cerebral oedema associated with brain cancer (peritumoral brain oedema). Corticorelin may be a safer alternative than the use of current treatments such as synthetic corticosteroids. In addition, the company believe the agent may enhance radiation therapy for brain tumours. Neurobiological Technologies licensed human corticorelin from the Salk Institute in the US. Various phase I/II trials have shown improvement in neurological function with corticorelin, which was well tolerated. In 1998, corticorelin received orphan drug status from the US FDA for the treatment of peritumoral brain oedema.

Endocytosis of hepatic lipase and lipoprotein lipase into rat liver hepatocytes in vivo is mediated by the low density lipoprotein receptor-related protein.

In isolated cell studies, the internalization and degradation of hepatic lipase (HL) has been linked to its binding to the low density lipoprotein receptor-related protein (LRP). We have utilized the receptor-associated protein (RAP), a universal inhibitor of high affinity ligand binding to LRP, to evaluate the participation of LRP in the endocytosis of HL and lipoprotein lipase (LPL). We isolated a total endosome fraction from rat livers after a 30-min infusion of recombinant RAP, administered as a glutathione S-transferase conjugate (GST-RAP). GST-RAP infusion had no effect on the concentration of HL in liver homogenates, but its concentration in blood plasma increased progressively by 20%, and enrichment over homogenate of HL in endosomes was reduced by 50% as compared with infusion of GST alone. The concentrations of LPL in liver and plasma were 1.4 and 0.5%, respectively, those of HL, but endosomal enrichment of the two enzymes was similar ( approximately 10-fold). GST-RAP infusion had no effect on the concentration of LPL in liver but increased its concentration in blood plasma by 250% and reduced its endosomal enrichment by 95% or greater. GST-RAP infusion also reduced endosomal enrichment of LRP by 40%, but enrichment of several other endocytic receptors was unaffected. Endosomal enrichment of several membrane trafficking proteins associated with the endocytic pathway in hepatocytes was unaffected by GST-RAP with the exception of early endosome endosome antigen 1, which was reduced by 85%. We conclude that HL is partially and LPL almost exclusively taken up into rat hepatocytes after binding to the endocytic receptor LRP.

S is for sticky

![Graphic][1] Centromeres fall apart (right) without Hsk1 action in S phase. Forsburg/MacmillanA kinase better known for triggering DNA replication also helps create the sticky heterochromatin at centromeres of fission yeast, according to Julie Bailis, Susan Forsburg (Salk Institute

Hirschsprung lost his nerve

Crone SA, Negro A, Trumpp A, Giovannini M, Lee K-F (The Salk Institute, La Jolla, California; Division of Biology University of California, San Diego, La Jolla, California; Hooper Foundation Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, California; and Institut Curie, INSERM U434 Paris, France). Colonic epithelial expression of ErbB2 is required for postnatal maintenance of the enteric nervous system. Neuron 2003;37:29–40.

An interview with Ronald M. Evans, Ph.D. Investigator, the Salk Institute for Biological Studies.

Dr. Ronald M. Evans is known for his original discoveries of nuclear receptor hormone receptors and the elucidation of their universal mechanism of action, a process that governs how lipophilic hormones and drugs regulate virtually every developmental and metabolic pathway in animals and humans. Dr. Evans obtained his Ph.D. in microbiology and immunology from the University of California, Los Angeles, School of Medicine and was a postdoctoral fellow at the Rockefeller University in New York. At Rockefeller, his studies on the transcriptional regulation of human adenovirus led to the identification of the first eukaryotic promoter for messenger RNA. In 1977, he joined the faculty of The Salk Institute for Biological Studies where he is an Investigator of the Howard Hughes Medical Institute and Professor in the Gene Expression Laboratory. He also holds the March of Dimes Chair in Molecular and Developmental Biology. In addition to his Salk appointment, he is an Adjunct Professor at the University of Califor...

Paul Berg—American Nobel Laureate

American biochemist and molecular biologist Paul Berg received the 1980 Nobel Prize in chemistry for “his fundamental studies of the biochemistry of nucleic acids, with particular regard for recombinant DNA.” In addition, he developed the new technology of genetic engineering. Berg shared the Nobel Prize with American chemist Walter Gilbert (1932-) and English chemist Frederick Sanger (1918-). Gilbert determined the sequence of bases in DNA by a method applicable to single- and double-stranded DNA, and Sanger determined the base sequence of nucleic acid. Sanger had previously won the 1958 Nobel Prize in chemistry for his work on the structure of proteins, especially insulin. Berg was born on June 30, 1926, in New York City. He received his secondary education at Abraham Lincoln High School and graduated in 1943. He entered Pennsylvania State University in University Park, but his education was interrupted for service in the US Navy from 1944 to 1946. After his discharge from the navy, he returned to Pennsylvania State University and graduated with a BS degree in biochemistry in 1948. Berg was a graduate student at Western Reserve University (now Case Western Reserve) in Cleveland, Ohio, and received a PhD degree in 1952. Berg spent 2 years (1952-1953) as a postdoctoral fellow at the Institute of Cytophysiology in Copenhagen, Denmark. After he returned from Denmark, he worked for 1 year with 1959 Nobel laureate Arthur Kornberg (1918-) at Washington University in St Louis, Mo. While working with Kornberg, Berg became familiar with the chemistry of DNA and RNA. He became an assistant professor of microbiology and remained at Washington University until 1959. In 1959, Berg left St Louis to become an associate professor at Stanford University in Stanford, Calif. In 1969, he was named chair of the biochemistry department. While at Stanford University, Berg became interested in the role of transfer RNA (tRNA), a substance that delivers amino acids to the proper position during protein assembly. Berg elucidated the role of tRNA in protein assembly by purifying many of the different tRNAs and the enzymes that link them to the correct amino acids. Berg took a sabbatical leave to work at the Salk Institute (La Jolla, Calif) with Italian virologist Renata Dulbecco (1914-), another Nobel laureate (1975 prize in physiology or medicine). His aim was to determine whether a method could be devised to examine and manipulate the complicated genes of multicellular organisms, including those of the human body. In 1968, Berg returned to Stanford University to begin his research on the genes of a monkey tumor virus. He began his first experiments on recombinant DNA about 1970. During the course of studying the action of isolated genes, he developed methods for splitting DNA molecules at selected sites and attaching segments of the molecules to the DNA of a virus or plasmid, which could enter bacterial or animal cells. The foreign DNA was incorporated with the host and caused the synthesis of proteins not ordinarily found there. The techniques that Berg and his colleagues developed enabled researchers not only to manipulate genes to create new pharmaceuticals, such as interferon and growth hormones, but also to study the molecular biology of more complicated organisms in detail. Berg has received many honors and awards in addition to the Nobel Prize. He was honored on a stamp issued by the Pacific islands of Palau in 2000.

The Sixth Annual Meeting of the American Society of Gene Therapy

thought to be a multistep process of sequential genetic lesions that take a cell from a normal phenotype through various stages of hyperplasia to a blatantly malignant phenotype—at least for solid tumor development. The development of leukemia may not necessarily follow such a path, and the adverse event in the French trial may eventually provide valuable information on the mechanism of leukemogenesis. Robert Weinberg presented this year’s Presidential Symposium, outlining work in his lab and others to understand the diversity and idiosyncratic nature of the genetic roadmap leading to cancer development in specific tissues, as well as the effects of surrounding tissues on the cancer cell. The Corporate Symposium this year focused on oncolytic viruses for cancer therapy, many of which have made their way to the clinic. While promising results have been obtained in many cases, a familiar theme was the need for better systems to evaluate these antitumor agents and the need to develop viruses that are more robust in their effects upon tumor cells relative to other cells of the host. Nevertheless, the symposium highlighted the slow but inexorable march of gene therapeutics out of the lab and into the complex world of clinical medicine. It would be impossible here to give more than a bird’s eye view of the work presented at this year’s meeting. With over 1200 abstracts submitted from laboratories around the world, the meeting represented the breadth of research into molecular and cellular therapies based on gene transfer and gene modification technology. Some may eventually work in patients, and many will not. However, as outgoing ASGT President Joe Glorioso stated in his farewell address to the attendees, “On balance, we are pioneering a new wave of genetic medicines. Progress is not without setbacks, and the path requires faith, innovation, stamina, and reason.”

Reminiscence

I gratefully acknowledge Dr. Maxwell Cowan's many contributions to my early career. During my third year of graduate school at the University of California San Diego, Dr. Cowan had just moved to the Salk Institute. While on his tour of the neuroscience laboratories in the area, Dr. Cowan came to visit the laboratory of my advisor, Rebecca Loy. During this time, I mentioned to him that the next step of my graduate studies was to determine the developmental time course of the cholinergic septohippocampal pathway. Not only did Dr. Cowan patiently listen to the prattling of a nervous graduate student but he invited me to come and carry out the studies in his laboratory with David G. Amaral. I couldn't believe my good fortune and quickly took him up on the offer. Dr. Cowan's laboratory was both environmentally and intellectually stimulating. While in Dr. Cowan's laboratory, I was able to learn several types of tract tracing, including 3H-proline anterograde transport, and the “proper” way to perform autoradiography. Little did I know at the time that I would still be using this technique! I think that the work I did in Dr. Cowan's laboratory under David's guidance set a high standard for my future scientific pursuits. I remember that, when I was just about to submit my paper for publication, Dr. Cowan had learned that a manuscript less thoroughly describing the development of the septohippocampal pathway was about to be published. As a graduate student, I was very disheartened, but Drs. Cowan and Amaral were quick to cheer me up. “Don't worry,” they said, “yours will be the study that people will remember.” They were right. To this day, this paper is still cited. Dr. Cowan also was instrumental in my selection of a laboratory for my postdoctoral studies. When it was time to decide my future after graduate school, Dr. Cowan took the time to sit down with me and discuss my plans. At that time, he gave me the names of three people that he thought would be good postdoctoral mentors. I also remember him saying that he thought I would like electron microscopy. Thus, following his advice, I went to work with Virginia M. Pickel at Cornell University Medical College. I wonder if he knew that 20 years later I would be using electron microscopy and still be working on the cholinergic septohippocampal pathway. —Teresa A. Milner

Fueling educational reform: Bio2010--biology for the future.

Fueling educational reform: Bio2010--biology for the future.

Can Better Diet Prevent Antisocial Behavior?

Back to table of contents Previous article Next article Clinical & Research NewsFull AccessCan Better Diet Prevent Antisocial Behavior?Joan Arehart-TreichelJoan Arehart-TreichelSearch for more papers by this authorPublished Online:2 May 2003https://doi.org/10.1176/pn.38.9.0043A few months ago, C. Bernard Gesch of Oxford University and coworkers reported in the British Journal of Psychiatry that vitamin-mineral-essential fatty acid supplements appeared capable of dampening violence in a prison population (Psychiatric News, October 2, 2002). However, J.S. Zil, M.D., J.D., chief forensic psychiatrist of the State of California Department of Corrections, told Psychiatric News that he was skeptical of their results. To which Gesch replied: “I don’t feel that Dr. Zil’s cynicism is a problem. It’s only natural to be cautious about such provocative findings.”And now here comes another study with similar thought-provoking results. It suggests that taking nutritional supplements during childhood might reduce antisocial behavior later.Adrian Raine, Ph.D.: “It could also be that it’s physical exercise, not better nutrition, that is the active ingredient.”The study was headed by Adrian Raine, Ph.D., a professor of psychology at the University of Southern California and a scientist noted for exploring the brain biology of criminals (Psychiatric News, March 3, 2000). Raine reported the investigation at the 9th International Congress on Schizophrenia Research, held recently in Colorado Springs, Colo., in a session on the neurobiology and management of violence in schizophrenia. The study is also in press with the American Journal of Psychiatry.This study, Raine explained, took place on a tropical island where the standard of living was quite low. It included 176 3-year-old children. Half the children served as a control group and received, from ages 3 through 5, their usual diets, usual exercise, and usual education. The other half served as an experimental group and received good nutrition, increased exercise, and an educational boost. The educational boost consisted of efforts to improve verbal skills, visuospatial skills, visuomotor coordination, creativity, conceptual skills, memory skills, and sensation and perception.Raine and his colleagues then tested the subjects for conduct disorder when they reached 17 years of age and found that there was significantly less conduct disorder in the experimental group. They also found that this effect was especially prevalent in the experimental subjects who had been malnourished at the start of the study.Raine and his coworkers again assessed subjects for criminal behavior at age 23. Self-reported crime was significantly reduced, by about 34 percent, compared with the control group. There was a trend for official crime to be statistically reduced to about a third of the levels of the control subjects.Thus, environmental enrichment appeared to reduce the incidence of conduct disorder, and perhaps also of criminal behavior, in these disadvantaged children, Raine and his colleagues concluded.E. Fuller Torrey, M.D.: “Something is going on in these children.”Peter Buckley, M.D., chair of psychiatry at the Medical College of Georgia and chair of the congress session, described the results as “provocative.” E. Fuller Torrey, M.D., of the Stanley Medical Research Institute in Bethesda, Md., the discussant for the session, said, “Something is going on in those children.”The question is, of course, what?Raine told Psychiatric News that the educational boost given the subjects may have made a difference. He also said, however, that he suspects that education is not the explanation since “past attempts [at using education to prevent antisocial behavior] have not been very successful in producing long-term change.”He said that exercise may have made a difference, since Salk Institute scientists recently found that rodents that exercised early in life had enhanced growth of neurons in the brain’s hippocampus.And how about nutrition? This is the explanation that Raine favors, particularly fatty acid supplementation. The experimental group ate lots of fish, he noted. Fish are rich in omega-3 and omega-6 fatty acids, and these acids influence the levels of serotonin and dopamine and are deficient in violent offenders. ▪ ISSUES NewArchived

Dr. Jonas Salk

Jonas Salk began his career in microbiology working with the inactivated influenza vaccine. He would later use the formalin inactivation process to create the poliomyelitis vaccine. Using a newly created modern cell culture technique, Salk was able to mass produce vaccines for the large-scale polio vaccine field trial. Under the direction of Thomas Francis, Jr., the field trial utilized both a double-blinded placebo-controlled trial and an observational study, and included almost 2 million American schoolchildren as subjects. The vaccine proved to be both safe and effective. Although later replaced by the Sabin oral vaccine, the Salk inactivated vaccine played a large part in the eventual eradication of polio from the Western Hemisphere. After his work on the polio vaccine, he created the Salk Institute, a private institution dedicated to research. Subsequently, until his death in 1995, Salk conducted research on an HIV vaccine.

C. elegans: the cell lineage and beyond.

Thank you so very much for inviting me to be here. It gives me a mingled sense – of humility at how much I owe to others, and of joy that the collective work on the worm has been recognised in this way. Among the first of my many mentors was my PhD supervisor, Colin Reese, who was developing non-aqueous methods for oligonucleotide synthesis (e.g. Fromageot et al., 1968). Colin passed me on to my postdoctoral supervisor Leslie Orgel at the Salk Institute, to work on prebiotic chemistry. The plan was to see to what extent we could copy RNA chains without enzymes. The products were in low yield, and the challenge was to work out the sequences that had been produced. We used cutting with different ribonucleases, and chromatography to separate the fragments (e.g. Sulston et al., 1968). My introduction to C. elegans came in 1969 with my move, at Leslie's suggestion, to Sydney Brenner's group at the Medical Research Council's Laboratory of Molecular Biology (Figure 1). Sydney was reputed to be setting

Worms and science. An interview with Sydney Brenner, distinguished research professor at The Salk Institute, La Jolla, USA, and one of the winners of 2002 Nobel Prize for Physiology and Medicine.

An interview with Sydney Brenner, Distinguished Research Professor at The Salk Institute, La Jolla, USA, and one of the winners of the 2002 Nobel Prize for Physiology and Medicine

Reply

Annals of NeurologyVolume 53, Issue 3 p. 421-421 Letters Reply Hongjun Song PhD, Hongjun Song PhD Molecular Neurobiology Laboratory, Howard Hughes Medical Institute at the Salk Institute, La Jolla, CA Laboratory of Genetics, The Salk Institute, La Jolla, CASearch for more papers by this authorD. Chichung Lie MD, D. Chichung Lie MD Laboratory of Genetics, The Salk Institute, La Jolla, CASearch for more papers by this authorCharles F. Stevens MD, PhD, Charles F. Stevens MD, PhD Molecular Neurobiology Laboratory, Howard Hughes Medical Institute at the Salk Institute, La Jolla, CASearch for more papers by this authorFred H. Gage PhD, Fred H. Gage PhD Laboratory of Genetics, The Salk Institute, La Jolla, CASearch for more papers by this author Hongjun Song PhD, Hongjun Song PhD Molecular Neurobiology Laboratory, Howard Hughes Medical Institute at the Salk Institute, La Jolla, CA Laboratory of Genetics, The Salk Institute, La Jolla, CASearch for more papers by this authorD. Chichung Lie MD, D. Chichung Lie MD Laboratory of Genetics, The Salk Institute, La Jolla, CASearch for more papers by this authorCharles F. Stevens MD, PhD, Charles F. Stevens MD, PhD Molecular Neurobiology Laboratory, Howard Hughes Medical Institute at the Salk Institute, La Jolla, CASearch for more papers by this authorFred H. Gage PhD, Fred H. Gage PhD Laboratory of Genetics, The Salk Institute, La Jolla, CASearch for more papers by this author First published: 24 February 2003 https://doi.org/10.1002/ana.10496Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Volume53, Issue3March 2003Pages 421-421 RelatedInformation

Things in their best order: technical aspects of the Salk Institute and their role in its design

This paper explores the integration of engineering, function and space in the Salk Institute for Biological Studies at La Jolla, California, USA, by Louis Kahn (1959–1967). While traditional interpretation has focused on the Salk’s courtyard as a space of uncanny emotional power, this study suggests that the power of this space derives in part from the intensity of Kahn’s attention to systems, materials and methods. Using drawings and project correspondence from the Louis I. Kahn archives at the University of Pennsylvania, the paper suggests an alternative understanding of Kahn’s work as empirical, evolutionary, and based as much in the prose of engineering as in the claimed poetics of architecture.

2002 Nobel Prize for physiology and medicine.

2002 Nobel Prize for physiology and medicine.

On cell biology, proteomics and career decisions.

On cell biology, proteomics and career decisions.