Dorothy Gietzen vividly remembers the day she caught the science bug.

"We were mixing copper oxides in Howard Vanderbilt's high school chemistry class, and they made the most beautiful blue colors," she recalls. "Right then, I was addicted to science."

Her love for science led her to study nursing — with a chemistry minor — and to become a public health nurse, serving several rural schools. Later, after raising five children, she went back to school at UC Davis, first for a master's degree in nutrition and then a doctorate in physiology, studying with Dorothy Woolley.

Later, while working as a postdoctoral fellow with Quinton Rogers, a biochemist and nutritionist in the School of Veterinary Medicine, the science bug bit once again and Gietzen discovered the question that would drive her research.

She became intrigued by a documented, but little understood, biochemical mechanism that allows animals to detect that their food is lacking in certain important amino acid building blocks for protein. As basic chemical units, amino acids are used by the animal's body to construct proteins for growth and development. Of the 20 amino acids found in animals, eight of them cannot be produced by or stored in the body and, therefore, must be obtained through the foods the animals eat. These eight are known as essential or "indispensable" amino acids.

Previous research has shown that animals can sense within a matter of minutes if their diet is deficient in an indispensable amino acid, making use of a subconscious sensing mechanism that does not depend on taste or smell. For example, if rats are offered more than one type of feed, and the first feed they try is deficient in an indispensable amino acid, they will soon switch to another feed that provides the necessary amino acids.

Inspired by the work of Dr. Rogers, and his mentor, the noted biochemist Alfred Harper from the University of Wisconsin, Gietzen decided in 1983 she would focus her research on discovering just how that deficiency-sensing mechanism worked. She realized that goal this year, when she and colleagues published in the March 18 issues of the journal Science a detailed explanation at the biochemical level, of just what makes that mechanism tick. The joy of the accomplishment is especially sweet because Gietzen will retire in June.

RNA signals cravings for more 'complete' foods

Information about the deficiency-sensing mechanism had been building for several decades.

Earlier research in Dr. Rogers' laboratory had demonstrated that the deficiency-sensing mechanism is headquartered in an area of the brain known as the "anterior piriform cortex," which is essential for behavioral responses such as those demonstrated by rats that stop eating a meal deficient in indispensable amino acids.

It was also known that living organisms have a system for using amino acids to build proteins. In this system, a molecule called transfer RNA carries the amino acids to the protein-synthesizing apparatus and may "interpret" the supply of amino acids for making proteins. When amino acids are available, the transfer RNA would be "charged," that is, bound to an amino acid as well as to an important enzyme in order to start the protein-building process. When an amino acid is not present, the transfer RNA is "uncharged." Earlier research with yeast suggested that an accumulation of uncharged transfer RNA initiates a signaling pathway that interrupts general protein manufacture.

Building on those findings, Gietzen and colleagues hypothesized that if uncharged transfer RNA provided the signal for indispensable amino acid deprivation, they could create the same signal by inhibiting the charging process. To do this, they injected rats with alcohol derivatives of amino acids to stall the charging process and then measured the animals' food intake. They found that following the injections, the rats stopped eating an amino-acid-complete feed as if it were deficient in an amino acid.

They also demonstrated that the effect of the injection could be reversed. After the injection-related tests were performed, they offered the rats a "corrected" diet that had high levels of the amino acid that had been targeted by the injected amino acid alcohol. They found that the corrected diet reversed the effects of the injection, and the rats continued eating.

The researchers further determined that the uncharged transfer RNA triggers the recognition of amino acid deficient diets by affecting two important proteins. The first is a kinase known as GCN2 that activates p-elf2a, which is crucial at the decision point between the initiation or blockade of protein synthesis.

In mammals, which cannot make their own essential amino acids, this signaling pathway alerts the neurons in the anterior piriform cortex area of the brain, so that the neurons can send a neurochemical signal to the animal's feeding circuitry in the brain. It is this signal that causes the rat to abandon a deficient feed and begin searching for something better.

Epilepsy research benefits as Gietzen passes torch

"Results from this study define the signaling pathway, well studied in yeast that, in mammals, tells the animal to go and look for a better food," Gietzen said. "Such a well-conserved biochemical pathway underscores the basic importance in a multitude of biological systems of keeping a supply of the building blocks for proteins readily available."

Clarifying how this signaling mechanism works is particularly important for research related to epilepsy, she said. Earlier research in her laboratory has shown that, in rats, dietary deficiencies in amino acids increase the severity of and susceptibility to epileptic seizures. Furthermore, the anterior piriform cortex is an area of the brain associated with high levels of neural excitability and the origin of seizures.

Gietzen notes that a colleague will be picking up where she left off with the epilepsy research. But Hank Gietzen, her husband of 52 years, says he will not be surprised if the lure of the lab is too much for his wife to resist, even in retirement. He knows all too well that one does not easily shake the bite of the science bug.