How do we remember? Memory research wins grand prize from Amersham biosciences and Science

November 29, 2001

Life-long learning and memory research--described by 27-year-old Song-Hai Shi, now working in San Francisco, California--earned this year's $25,000 Young Scientist Prize, awarded by Science and Amersham Biosciences (formerly Amersham Pharmacia Biotech).

Just as weight-training strengthens muscles, learning opportunities "train" our brains to store and process massive amounts of information, researcher Song-Hai Shi explains in his winning essay, to be published in the 30 November 2001 issue of Science.

This brain-strengthening process, described by scientists as the "long-term potentiation" of connections, may help explain how best to promote memory and learning-and, perhaps someday, why memory can falter, said Shi, now a Howard Hughes Medical Institute research associate at the University of California at San Francisco.

Shi was a graduate student from the State University of New York at Stony Brook, working in the laboratory of Roberto Malinow at Cold Spring Harbor Laboratory, when he first began studying brain connections called synapses. He wanted to know exactly what causes long-lasting changes in transmissions by these connections. In the brain's hippocampus region, such transmission changes help us form new memories.

In his early work, Shi demonstrated that nerve-cell stimulation-similar to the brain stimulation caused by learning-triggers the rapid relocation of receptors for the neurotransmitter glutamate, a key player in synaptic communications. Excitation prompts a chemical "priming" process called long-term potentiation (LTP). In response, unleashed receptors quickly move from nerve-cell interiors to the surfaces of branch-like arms (dendritic spines), which protrude from neurons, Shi showed. This rapid delivery of AMPA type receptors (a-amino-3-hydroxy-5-methyl-4-isoxazole propionate) depends on the activation of another glutamate receptor, NMDA (N-amino-D-aspartate), Shi and his colleagues explained in Science on 11 June 1999.

But, do AMPA receptors actually help to strengthen synapses and, therefore, memory? On 24 March 2000, Shi and his colleagues again reported in Science that AMPA receptors are incorporated directly into synapses following long-term potentiation.

Key to these findings was the novel method for fusing a subunit of the AMPA receptor, called GluR1, with green fluorescent protein, and then "growing" the recombinant receptor in neurons with a viral expression system. High-tech microscopy revealed the location of these fluorescing receptors, which quickly converged to dendritic spines following electrical stimulation.

To further track the fate of AMPA receptors, researchers over-expressed receptors containing the GluR1 subunit, which allows ions to flow into cells, but not the subunit, GluR2, which lets ions to escape. Sure enough, increased in-flow of ions into cells showed that AMPA receptors were being incorporated by synapses. Shi and his collaborators also explained how delivery of AMPA receptors to synapses, mediated by the protein kinase, CaMKII, depends on the interaction of PDZ domain proteins and the intracellular carboxyl terminus of receptors. Shi's work revealed that AMPA receptors containing the GluR1 subunit may be replaced by receptors with the GluR2 subunit, resulting in a long-lasting increase in synaptic transmission.

"These studies attempt to define the molecular signature of synaptic plasticity so that it may be possible to examine when and where this process occurs in the brain during behavioral modification," Shi said. "We may eventually be able to answer: how do we remember?"

Amersham Biosciences, a leading global provider of integrated systems and solutions for disease research and drug development, joined with Science to establish the Young Scientist Prize in 1995. Each year, the Prize supports molecular biologists in an early stage of their careers.

In addition to the Grand Prize, a judging panel may present regional awards of $5,000 each to researchers within four geographic regions: North America, Europe, Japan, and all other countries. This year, the regional prizes recognized discoveries about smallpox spread and cell motility, life after cell death, and more.

Andrew Carr, CEO of Amersham Biosciences, commented: "Song-Hai Shi's elegant study of receptor dynamics and synaptic plasticity demonstrates the potential of next-generation investigators, whose new ideas and enthusiasm can spark important fundamental discoveries. Through the Young Scientist Prize, Amersham Biosciences and Science seek to reward such early accomplishments, and promote further advances to benefit human welfare."

Monica Bradford, managing editor of Science, added that "breakthrough thinking by young scientists like Song-Hai Shi can trigger a chain-reaction of discovery, as other researchers seek to replicate and further investigate the new findings. At Science, we are proud to be collaborating with Amersham Biosciences, to support the next-generation of researchers."

Applicants for the Prize must have earned their PhDs during 2000 and had submitted a 1,000-word essay based on their dissertations. Essays are judged on the quality of research, and the applicants' ability to articulate how the work would contribute to the field of molecular biology, which investigates biological processes in terms of the physical and chemical properties in a cell.

Amersham Biosciences and Science named five regional winners to receive $5,000 awards:

EUROPE / Smallpox Spread: One of history's most devastating diseases, smallpox killed 300 million people in the 20th century before it was eradicated in 1977. How did smallpox so effectively spread from victim to victim? Research by Friedrich Frishknecht and colleagues at the European Molecular Biology Laboratory in Heidelberg, Germany, now a postdoctoral associate at the Pasteur Institute in Paris, showed that vaccinia--the harmless cousin of smallpox--moves from cell to cell by commandeering the cell's cytoskeleton. Specifically, vaccinia hitches a ride on the tip of filaments of the fiber-forming protein, actin. By activating its viral coat protein, vaccinia then prompts the assembly of adjacent actin fibers--thus, fooling the cell, which reacts as if it received a signal for cell movement. When the cellular "door" opens, however, vaccinia pushes the hijacked actin filament into the cell membrane. The pathogens, Listeria monocytogenes and Shigella flexneri use similar cell motility methods, said Frishknecht, who was raised in Bad Urach, Germany, and plans a pursue a career in parasitology.

EUROPE / Pancreatic Development and Diabetes: Understanding how the pancreas develops is important for disease research. Diabetes, affecting more than 3 percent of the world's population, occurs when something goes wrong in the pancreas, so that the body, for example, may produce too little insulin, which converts sugars and starches into energy. To learn more, University of Umea researcher Åsa Apelqvist began studying the signals that certain molecules send as the pancreas develops in mice. She also wanted to better understand beta-cells, which help produce insulin in the pancreas. Apelqvist, now working in the Department of Developmental Biology at the Beckman Center, Stanford University, found that signalling through the fibroblast growth factor receptor 1c (FGFR1c) was crucial for functioning pancreatic beta cells. Mice with a defect in this receptor developed diabetes, similar to the problems associated with type 2 diabetics among humans. Earlier, Apelqvist showed that another signalling process (notch-signalling) controlled the formation of various pancreatic cell types, and she identified the transcription factor, Neurogenin3, as the pro-endocrine gene. Someday, this finding might suggest a way to create beta cells for people who don't have enough to produce the insulin that our bodies need. Apelqvist further showed that the signalling molecule, Sonic hedgehog (Shh) was expressed throughout the gut tube, except at pancreatic levels. Using transgenic techniques, she found that Shh negatively influences pancreatic development.

NORTH AMERICA / Cell Death and Tumors: New therapies aimed at activating the body's immune system against cancerous tumors may soon emerge from work by Matthew L. Albert and colleagues at The Rockefeller University in New York City. To learn how the body fights off cancer, Albert studied an immune-system response in patients with a rare syndrome called Paraneoplastic Neuronal Degenerations (PNDs), which can cause cerebellar degeneration, dizziness, weakness and other symptoms as the patient's body targets an invading tumor. Albert showed that dendritic cells can stimulate killer T cells (cytotoxic T lymphocytes) into action. To do this, apoptotic or dying cells signal dendritic cells to consume them. The fragments are then presented to killer T cells, prompting an immune response that results in naturally occurring tumor immunity. More recently, Albert and his collaborator, Robert B. Darnell, have explained how the absence or presence of "helper T cells" can switch killer T cells on or off-telling them to attack or retreat. That is, when dendritic cells present apoptotic cell fragments to killer T cells in the presence of helper T cells, the killer T cells attack the invader. But, when helper T cells aren't around, the killer T cells "tolerate" the antigen, thus avoiding an autoimmune attack. Someday, Albert imagines, new anti-tumor therapies may involve, for example, injecting dendritic cells and dying tumor cells into a patient, to turn on killer T cells. Similarly, turning off such killer T cells may suggest a route for fighting autoimmune disorders.

JAPAN / Cellular Guidance Systems: As an organism takes shape, two types of secreting ligands or atom groups--morphogens and chemotropic factors--seem to direct traffic, telling cells "where they are" and "where to go," respectively. In fact, the concentration of morphogens versus chemotropic (diffusible) factors may act as a kind of global positioning system for cells. But, exactly how these ligands support cell differentiation through positional information remains a central mystery of developmental biology. Masaki Hiramoto of Japan's National Institute of Genetics investigated several possible scenarios in an effort to learn more about the function of morphogens and chemotropic factors. Some evidence supports the Chemotropic Hypothesis, which suggests that during development, diffusible matter secreted from the spinal cord forms a concentration gradient that attracts the transverse nerve toward the basal plate. Hiramoto also explored guidance scenarios based on the seizure of ligands by receptor molecules: Much like pulling a car's steering wheel in one direction, ligand seizure tends to contribute to asymmetrical ligand distribution in models such as the fruit fly. Finally, Hiramoto examined a second function of receptors in patterning, in which the receptor exhibits the ligand, and then guides the next step of development: For example, positional adjustments occur when the molecule, "Frazzled," recognizes and seizes the secretory molecule, Netrin.

ALL OTHER COUNTRIES (Israel) / DNA Replication: Replication of life's blueprint, DNA, allows genetic information to be passed from cell to cell. Why do some regions replicate earlier than others, and what controls the timing of replication? Research by Itamar Simon, completed at the Hebrew University medical school, Jerusalem, Israel, helps explain the significance of the precise timing of replication events, and their role in regulating the expression of various genes. Early DNA replication correlates strongly with gene expression, and thus, replication is thought to affect transcription. Simon's work demonstrates that replication timing helps regulate gene expression of large genomic regions, particularly in cases where differentiation between two identical alleles (two copies of a gene) is needed, such as with olfactory receptor genes and parentally imprinted genes. Simon's research is continuing at The Whitehead Institute, Cambridge, Massachusetts.
-end-
Science, a leading international weekly covering all disciplines, is published by the American Association for the Advancement of Science (AAAS), the world's largest general scientific organization. Science has the largest paid circulation of any peer-reviewed general scientific journal in the world.

Amersham Biosciences, the life sciences business of Amersham plc (LSE, NYSE, OSE: AHM), is a world leader in developing and providing integrated systems and solutions for disease research, drug development and manufacture. Our systems are used to uncover the function of genes and proteins, for the discovery and development of drugs and for the manufacture of biopharmaceuticals. The customers for Amersham Biosciences' products and technology are pharmaceutical and biotechnology companies and research and academic institutions, principally in North America, Europe, Latin America, and Asia. Information about the prize, and winning essays, will be posted on Science Online (http://www.sciencemag.org/feature/data/pharmacia/prize/apbprize.shl), available 30 November.

Media Contacts: AAAS/Science--Ginger Pinholster, 202-326-6421, gpinhols@aaas.org; Amersham Biosciences--Marcy Saack, 732-457-8056, marcy.saack@am.amershambiosciences.com, or Linda van Manen, +31-165-580-445, linda.vanmanen@eu.amershambiosciences.com Amersham Biosciences-Marcy Saack 732-457-8056 / marcy.saack@am.amershambiosciences.com

American Association for the Advancement of Science

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