Leaders in Pharmaceutical Business Intelligence (LPBI) Group

Stress-response gene networks

Larry H Bernstein, MD, FCAP, Curator

Leaders in Pharmaceutical Intelligence

Series E. 2; 3.6

Nina V. Fedoroff
Evan Pugh Professor of Biology, Willaman Professor of Life Science
Ph.D., The Rockefeller University, Molecular Biology , 1972

After graduating from Rockefeller University she joined the faculty of the University of California, Los Angeles, where she did research into nuclear RNA.^[10] She then worked on developmental biology at the Department of Embryology at the Carnegie Institution for Science in Baltimore, Maryland, USA, where she pioneered DNA sequencing and worked out the nucleotide sequence of the first complete gene.^[10] In 1978, she became a staff member at the Carnegie Institute and joined the faculty of Johns Hopkins University Biology Department, where she did groundbreaking work on the molecular characterization of maizetransposable elements or jumping genes (for which Barbara McClintock had been awarded a Nobel Prize in 1983).^[10]

Fedoroff has been honored with the Howard Taylor Ricketts Award from University of Chicago in 1990,^[4] and in 1992 she received the New York Academy of Sciences Outstanding Contemporary Women Scientist Award.^[4] In 1997, Fedoroff received the John P. McGovern Science and Society Medal from Sigma Xi.^[9] She was awarded in 2003 Syracuse University‘s George Arents Pioneer medal.^[9]

President Bill Clinton appointed Fedoroff to the National Science Board, which oversees the National Science Foundation, in 2001.^[4] The foundation administers the science awards, established by the United States Congress in 1959. Fedoroff was Science and Technology Adviser to U.S. Secretaries of State, Condoleezza Rice and Hillary Clinton^[13] and to the administrator Rajiv Shah for the United States Agency for International Development from 2007 to 2010.^[14]

A major project in the laboratory is investigating the responses of plants to biotic (pathogens) and abiotic (ozone, temperature, chemicals) stresses using DNA microarray gene expression profiling and reverse genetics. We have identified more than 1,200 stress-modulated Arabidopsis genes, and we are studying their expression under various conditions. Among the genes induced by various stresses are signaling genes, transcription factors, and effector genes that include enzymes that alter the cells structure and properties in response to stress. The signaling molecules include MAP kinases and receptor-like kinases. We are suppressing and overexpressing potential regulatory genes to identify the genes under their control. We want to understand the structure of the stress-response gene networks and to explore molecular-genetic approaches to modifying the stress response (see Holter et al., 2000, 2001).

Hormone Responses

The hyl1 Arabidopsis mutant has a transposon insertion mutation in a gene that is involved in several hormonal signaling pathways, including those for abscisic acid, auxin, and cytokinin. The mutant is affected in many growth parameters, including graviperception. It is not as sensitive to exogenous auxins and cytokinins as the wildtype, but it is hypersensitive to abscisic acid. The HYL1 protein binds to double-stranded RNA and localizes to the nucleus. The mutant is described in Lu and Fedoroff (2000). We are investigating how this protein affects hormone signaling.

Transposable Elements

Transposable elements or transposons were discovered in corn (maize) plants by the famous geneticist Barbara McClintock through classical genetic analysis of unstable mutations (for a brief history, see http://www.ergito.com or Fedoroff 2001). Maize transposons were cloned in our laboratory almost 20 years ago and are now widely used for insertional mutagenesis. We have created a database of several hundred Arabidopsis transposon insertion lines using a transposon tagging system developed in the laboratory (Smith et al., 1996; Raina et al., 2001).

Epigenetic Mechanisms

The maize Suppressor-mutator (Spm) transposon is epigenetically inactivated by methylation and encodes a protein, TnpA, which is capable of reversing the inactivation (Schläppi et al., 1994; Fedoroff et al., 1995). Using an inducible promoter to express TnpA, current experiments seek to understand how TnpA demethylates the Spm promoter. Some ideas about plant transposon evolution are explored in Fedoroff (2000).

The World Food Prize laureates for 2013 were announced in June. They are Marc van Montagu, Mary-Dell Chilton and Rob Fraley. These scientists played seminal roles, together with the late Jeff Schell, in developing modern plant molecular modification techniques. Fraley is chief technology officer of Monsanto. Chilton is a Distinguished Science Fellow at Syngenta. Montagu founded Plant Genetic Systems (now part of Bayer CropScience) and CropDesign (today owned by BASF).

Van Montagu and Chilton independently developed the technology in the 1980s to stably transfer foreign genes into plants, a discovery that set up a race to develop tools to genetically engineer plants. It allowed other scientists to incorporate genetic traits in plants to better withstand drought, extreme heat and to fight off pests and disease. Fraley was the first to successfully transfer immunity to specific bacteria into a plant.

Fraley genetically engineered the first herbicide-resistant soybean in 1996.

The three laureates (and their colleagues) developed molecular techniques for plant genetic modification. We can now use these methods to make precise improvements by adding just a gene (or two or a few) that codes for proteins whose function we know with precision. Yet plants modified by these techniques, the best and safest we’ve ever invented, are the only ones we now call GM. Almost everyone believes we’ve never fiddled with plant genes before, as if beefsteak tomatoes, elephant garlic and corn were somehow products of unfettered nature.

If the popular mythology about farmer suicides, tumors and toxicity had an ounce of truth to it, these companies would long since have gone out of business. Instead, they’re taking more market share every year. There’s a mismatch between mythology and reality. Maybe it’s worth remembering that technology vilification is about as old as technology itself. What’s new is electronic gossip and the proliferation of organizations that peddle such gossip for a living.

Author: Nina Fedoroff is distinguished professor of biosciences at the King Abdullah University of Science and Technology in Saudi Arabia and Evan Pugh professor at Penn State University. She has no material interest in Monsanto or its products.

Nina Fedoroff did her undergraduate work at Syracuse University, graduating summa cum laude with a dual major in biology and chemistry. She attended the Rockefeller University, where she earned her Ph.D. in Molecular Biology in 1972. Both her undergraduate research at Syracuse University and her graduate research on RNA bacteriophage at The Rockefeller University were supported by grants and fellowships from the National Science Foundation. Following graduation from The Rockefeller University, she joined the faculty at the University of California, Los Angeles (UCLA), and carried out research on nuclear RNA. In 1974 Fedoroff received fellowships from the Damon Runyan-Walter Winchell Cancer Research Fund and the National Institutes of Health (NIH) for postdoctoral work, first at UCLA and then in the Department of Embryology of the Carnegie Institution of Washington in Baltimore. Working in the laboratory of Donald Brown, Fedoroff pioneered in DNA sequencing, determining the nucleotide sequence of the first complete gene. In 1978, Fedoroff became a staff member of the Carnegie Institution of Washington and a faculty member in the Biology Department at Johns Hopkins University. Her research focus changed to the molecular characterization of maize transposable elements. The isolation of the maize transposons, discovered genetically by Barbara McClintock in the 1940s, was achieved in the early 1980s. In subsequent years, Fedoroff’s lab showed that the maize transposons were active in a variety of other plants, developed transposon tagging systems, and studied the epigenetic regulation of transposon activity. In 1995 Fedoroff joined the faculty of the Pennsylvania State University as Willaman Professor of Life Sciences.