Clock cues: Cellular sensing, metabolism research wins Amersham Biosciences and Science Prize

November 20, 2002

All of us live our lives on the circadian clock, an interacting group of molecules that regulates the body's activities on a 24-hour cycle. This daily rhythm can be influenced by environmental cues-such as light, energy status, and food availability-through a special cellular sensing system described for the first time by Jared P. Rutter of the University of Texas Southwestern Medical Center, winner of this year's $25,000 Young Scientist Prize awarded by Amersham Biosciences and Science.

These discoveries point to "a way for an organism, down at the cellular level, to respond to changes in its environment in a fairly rapid way, and to maintain its proper activity rhythm," said Rutter, who noted that changes in the circadian cycle in humans have been associated with sleep disorders and depression.

Rutter and his Ph.D. advisor Steven L. McKnight arrived at the UT Southwestern lab at the same time with no established projects to work on and the freedom to explore research problems that few other labs were pursuing.

"That's been one of the most exciting, and most rewarding, parts of my work, to look back at starting from scratch and actually see some headway in understanding the biology," said Rutter.

"Biological rhythms and their underlying mechanisms have become an exciting domain in neuroscience and cell biology. Rutter's work has provided an important new insight that will enhance the excitement," said Science Editor-in-Chief Donald Kennedy.

Rutter examined two proteins in his research, both containing a "sensing" domain known as a PAS domain. The first protein, NPAS2, is involved regulating the body's 24-hour cycle. Rutter discovered that NPAS2 acts as a bridge between the expression of circadian cycle genes and the cell's metabolic environment, by linking itself to a heme molecule that acts as a gas sensor in the cell. Production of gases like carbon monoxide is likely to fluctuate depending on a cell's metabolic activity.

In a paper appearing in the 21 November issue of Science Express, Rutter and others show that exposure to carbon monoxide affects NPAS2's ability to bind with a clock protein called BMAL1, which in turn affects the expression of certain circadian cycle genes.

But one PAS wasn't enough: Rutter also took on the challenge of uncovering the biological role for an enzyme called PAS kinase. After extensive studies of the enzyme in yeast, Rutter found that PAS kinase regulates sugar storage and protein manufacture in cells. When PAS kinase is activated by an unknown small molecule, it blocks sugar storage and stimulates protein synthesis.

The unknown "trigger" molecule is likely to be some kind of nutrient essential to growth, making PAS kinase another important sensor of a cell's metabolism, according to Rutter.

Rutter said that he was "completely shocked" by the news that he had won the Grand Prize. He's uncertain about what to do with the prize money, but admits that he and his wife may take a trip to Europe to celebrate.

"I have looked at previous winners, and I don't think that I compare. Winning this is as much a comment on Steve and the other lab members and UT Southwestern Medical Center as it is on me," said Rutter.

"As a scientist and researcher, I was very impressed with Jared Rutter's study of the circadian rhythms. In fact, all of the winning entries this year really make a researcher, no matter the years of experience, sit back and think," said Andrew Carr, President, Amersham Biosciences. "This prize is dedicated to recognizing the up and coming researchers behind future of molecular medicine, and this year's winners will clearly have an impact."

Amersham Biosciences and Science established the Young Scientists' Prize in 1995 to provide support to molecular biology scientists at an early stage of their careers. In addition to the Grand Prize, the judging panel may present regional awards of $5,000 each to researchers within four geographic regions: North America, Europe, Japan, and all other countries.

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

JAPAN/Immune Bone-Breakers: New insights into links between the immune system and bone biology explored by Hiroshi Takayanagi at the University of Tokyo may be the beginnings of a fruitful new field of research: osteoimmunology. Takayanagi studied how certain immune molecules can influence the production of osteoclasts, bone-destroying cells that play an important part in normal bone growth as well as diseases such as osteoporosis. His work on bone metabolism may also suggest targets for the treatment of autoimmune conditions like rheumatoid arthritis.

JAPAN/Ferrying Cargo in the Brain: The brain contains a busy transportation system that shuttles neurotransmitters and other proteins between neurons using a variety of molecular motors, making the biochemical connections that underlie memory and learning. But are these motors "equal opportunity" carriers, or do they recognize and carry specific cargo? Mitsutoshi Setou of the University of Tokyo examined this question in a group of long-distance neuronal motors known as KIFs, finding that KIFs do participate in a specific cargo recognition system.

EUROPE/Viral Silencing: Short snippets of RNA can suppress gene expression in a phenomenon known as RNA silencing. Now, Olivier Voinnet suggests that RNA silencing may act as a general antiviral system in plants and probably animals as well. Voinnet's research at the Sainsbury Laboratory in Norwich, UK, demonstrated that when an invading virus triggers a silencing response at a local point in the host plant's genome, a previously unknown "signal" spreads the silencing throughout the rest of the genome. Voinnet also showed that viruses encode proteins that fight against silencing, uncovering an arms race between viral and host DNA.

EUROPE/Sisters Stick Together: The critical process of cell division requires that replicating and dividing chromosomes pair up correctly before finding their way into new cells. Sister chromatids-the two strands that make up a chromosome, must stick together during this process. At the University of Vienna in Austria, Attila Toth designed a large screening study to identify several previously unknown proteins involved in sister chromatid cohesion. Toth continues his work at the University of Cambridge, UK.

NORTH AMERICA/RENT Control: The finale of cell division is another crucial but poorly understood phenomenon, but Wenying Shou's work at the California Institute of Technology has helped shed light on the molecular mechanisms that govern the end of mitosis. After isolating several mutants within a group of genes called the mitotic exit network (MEN), Shou concluded that MEN controls the end of cell division by transmitting a signal to dismantle a protein complex dubbed RENT, which keeps the cell from ending mitosis prematurely. Shou, now at Rockefeller University, submitted two essays for prize consideration: one traditional description of her research, and a second, humorous "selected diary" written from the point of view of her yeast study subjects.

ALL OTHER COUNTRIES (Israel)/Expanding the Antibody Repertoire: The immune system defends the body against a wide variety of insults and invasions by generating a vast repertoire of antibodies. To produce these unique antibodies, the immune system restricts gene rearrangements to only one of two possible versions (alleles) of each gene in newly created B cells. At the Hebrew University in Israel, Raul Mostoslavsky studied the molecular mechanisms behind how the immune system singles out which allele to select for rearrangement. Mostoslavsky continues his work at the Children's Hospital in Boston, Massachusetts.
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 science 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 technologies 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, available 20 November.

American Association for the Advancement of Science

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