Saba Valadkhan of Case Western Reserve University Wins Young Scientist Award
For correctly identifying "a relic from the RNA world" and proving its catalytic potential thus, solving a molecular riddle that has baffled others for two decades Saba Valadkhan today was named to receive the $25,000 Young Scientist Award, supported by GE Healthcare and the journal Science.
She will receive her award this weekend during the 2005 Annual Meeting of the American Association for the Advancement of Science (AAAS), world's largest general science society, which publishes Science. [Read the text of an extended interview with Valadkhan here.]
"Saba's discovery was akin to finding the Holy Grail of the splicing catalysis field," said Professor James L. Manley of Columbia University in New York City, who supervised her graduate work. "Obtaining catalytic activity from purified small nuclear RNAs had been attempted many times over the years in many of the major splicing labs around the world, which underscores the significance of her accomplishments."
DNA, life's genetic blueprint, drives most modern biological events, along with proteins, and is generally considered the primary repository for genetic information. But, many scientists believe that DNA's modern-day messenger, RNA, played a far more dominant role in ages past, before handing over most of its biological functions to DNA and proteins.
To rule the biological world, RNA needed to serve as an enzyme, capable of catalyzing a wide range of chemical reactions, explained Valadkhan, an Iranian-born scientist who is now an assistant professor in the Center for RNA Molecular Biology at Case Western Reserve University in Cleveland, Ohio. In fact, pre-messenger RNA splicing plays an important role in many aspects of cell growth control, differentiation and disease. This splicing reaction is catalyzed by the most complex cellular machine known, the spliceosome, a big ribonucleoprotein particle composed of some 300 proteins and five RNAs.
But, where and how does the spliceosome's catalytic activity occur? For two decades, scientists had been investigating two of the spliceosome's small nuclear RNAs (snRNAs), called U2 and U6, as the most likely candidatesyet, without any proof, until Valadkhan's relentless quest for the answer.
Her graduate research involved building the spliceosome's active site from scratch, by bringing together U2 and U6, then proving their catalytic action, by producing a novel RNA species, RNA X. More recent study has yielded another interesting product, RNA Y, which is still being characterized. Collectively, Valadkhan said, her findings "proved that the spliceosome is an RNA enzyme and a relic from the RNA world."
Valadkhan "is an enormously talented young scientist with all the qualitiesintelligence, dedication and imaginationthat it takes to make significant and meaningful discoveries in the field of molecular biology," Manley said of his former student. "Strikingly, with careful planning, experimentation and persistence, Saba succeeded in establishing that purified U2 and U6 snRNAs do indeed have catalytic activity, and can promote a reaction related to the first step of splicing."
While finally proving the catalytic potential of the two spliceosomal snRNAs, Valadkhan also developed a powerful new tool for further investigations of this crucial cellular machine and its evolution.
Born outside Tehran, Valadkhan's early studies focused on medical training, but she said that she switched to science partly in hopes of increasing the impacts of contributions. "If you want to have a real impact on healthcare, you can be a doctor and treat people, one by one," she said, "or you can become a scientist and make discoveries that could someday tell us something about disease, for example. So, I thought that I could potentially have an impact on many more people, as a scientist."
Christoph Hergersberg, global technology leader of biosciences at GE Global Research, commented: "Saba Valadkhan's accomplishments are an inspiration to her peers, to senior scientists and to the next generation of investigators alike. Her work shows that the young scientists drive the progress. GE Healthcare is proud to support this progress through the Young Scientist Award."
Donald Kennedy, Editor-in-Chief of Science, said: "Science is delighted to recognize Saba Valadkhan's outstanding contribution to molecular biology. Her discovery will benefit a generation of scientists investigating RNA and, in fact, the biological origins of life on Earth."
Each year since 1994, the Young Scientist Award has recognized outstanding young molecular biologists at an early stage of their careers. Some 48 young scientists have so far received the award, honoring exceptional thesis work in the field of molecular biology.
Applicants for the 2004 Young Scientist Award earned their Ph.D.s in 2003 and submitted a 1,000-word essay based on their dissertations. Their essays were judged on the quality of research and the applicants' ability to articulate how their work would contribute to the field of molecular biology, which investigates biological processes in terms of the physical and chemical properties of molecules in a cell.
A judging panel selects the Young Scientist Award grand prize winner and may present regional awards in four geographic regions: North America, Europe, Japan and all other countries. These regional winners receive $5,000 awards. In addition to the grand prize, the 2004 Awards also recognized the following regional winners:
Kunihiko Nishino (Japan): To better understand drug-resistant bacteria, Kunihiko Nishino studied genes that code for "drug exporters," which thwart antibiotics by expelling them from infected cells. First, he identified 37 Escherichia coli genes that may play a role in drug resistance, including 10 that had never previously been identified. The 10 newly identified resistance genes were shown to recognize novel antibiotics under development by pharmaceutical companies.
Ultimately, his investigations focused on one drug exporter, MacAB, which expresses a protein that resists certain macrolide antibiotics. MacAB achieves its resistant function by forming a complex with a protein called TolC, Nishino reported. Understanding this particular drug exporter's ability to resist antibiotics is important because infectious pathogenic bacteriasuch as Salmonella typhimurium, Yersinia pestis, and Pseudomonas aeruginosaall have proteins similar to MacAB that are thought to play a role in drug resistance, he explained.
Nishino found that "two-component signal transduction systems" trigger the expression of drug-resistance agents on 15 of 32 signal transduction regulator genes coded by the E. coli gene. Further, he identified a protein, H-NS, that seems to be yet another player in drug exportation that is expressed at different times. "These results may provide useful information for proactive treatmentgiving suitable antibiotics at an optimum timing," he said. Nishino's work was conducted under the direction of Dr. Akihito Yamaguchi at Osaka University. Nishino is now with the Howard Hughes Medical Institute at Washington University School of Medicine.
Suvendra Nath Bhattacharyya
Suvendra Nath Bhattacharyya (All Other Countries): The ingenious discovery of a molecular motor that might someday be harnessed to repair damaged genes in people with certain neuro-myopathic diseases earned a regional Young Scientist Award for Suvendra Nath Bhattacharyya, whose work was completed at the Indian Institute of Chemical Biology, Calcutta, India.
His work could set the stage for engineering human mitochondria, which contains life's blueprint, to import gene-repair molecules (tRNA) into the cells of people with certain diseases, to fix faulty genetic translation. The work, conducted under the direction of Dr. Samit Adhya, also could lead to new tools for controlling pathogenic parasites such as Leishmania and Trypanosoma, which are responsible for widespread human diseases but lack mitochondrial tRNA genes.
Bhattacharyya used Leishmania as a host to study the movement of tRNA into the mitochondrion. He identified two classes of biochemical signals that help or hinder tRNA's progress toward the mitochondrion, while also maintaining a balanced pool of tRNAs in the organelle. He purified a large functional protein complex, RNA Import Complex, or RIC, that plays a role in helping tRNA gain entry to the mitochondrion.
Specifically, he reported, the import complex serves as "a molecular motor." The tRNA switches on the motor, which uses an enzyme action, ATP hydrolysis, to stimulate translocation of protons. In this way, tRNA triggers the opening of a passage-way for tRNA.
Benjamin P. Tu
Benjamin P. Tu (North America): Tu's investigations have shed new light on the fundamental biological process of protein folding, and revealed a possible major source of oxidative stress to certain cells, too. His winning studies of sulfur-to-sulfur or "disulfide" bonds focused on a particular organelle inside cells a complex network of membranes called the endoplasmic reticulum (ER) that folds and transports many of the cell's proteins.
Tu determined the mechanism by which the ER supports the formation of sulfur-to-sulfur bonds, a problem that had remained unsolved for the past 40 years. As many as one-third of the proteins encoded by the human genome may depend on sulfur-sulfur bonds for proper folding and function, Tu noted. He reported that the membrane-related protein, Ero1, "harnesses the reducing potential of molecular oxygen to drive disulfide bond formation."
From a scientific standpoint, Tu said, "it seems elegant that cells have evolved a system to couple disulfide formation to the strong reduction potential of molecular oxygen." Unfortunately, he added, the process can create oxidative stress, damaging macromolecules and causing cellular dysfunction and even cellular death, suggesting that cells must carefully regulate disulfide formation Tu conducted his work under the direction of Dr. Jonathan S. Weissman at the University of California, San Francisco. He currently works at the University of Texas Southwestern Medical Center, Dallas.
Christian Haering (Europe): Every time a cell divides, it must give rise to two daughter cells that inherit its complete genetic blueprint. The two identical copies of each of the cell's DNA molecules resulting from DNA replication, the sister chromatids, are held together by tight connections. A protein complex called cohesin is responsible for these connections.
Haering's work described how the proteins of the cohesin complex (Smc1, Smc3, Scc1 and Scc3) form a large loop, or ring structure. The ring might be used to trap sister chromatids inside its embrace, thereby holding them together. Cohesin belongs to a family of chromosomal protein complexes, conserved from bacteria to humans, that all contain SMC proteins.
The results may therefore offer a "universal solution to the mystery of how these ancient protein complexes organize chromosomes in every living organism," he said. The research was conducted under the direction of Professor Kim Nasmyth at the IMP and University of Vienna. Haering is now at the University of Oxford, U.K.
10 February 2005