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Media Contact: UC San Diego
Greg La Brache glabrache@ucsd.edu
Tel: 858-822-3075

NEW GENETIC CIRCUIT RESEARCH MAY HELP DEVELOP MEDICATIONS TO BEAT DRUG-RESISTANT BACTERIA

UC San Diego Research Results Just Published In The Journal of Biological Chemistry

SAN DIEGO, CA--(June 23, 1999)-- Itís a clear healthcare problem affecting millions of people around the globe--dangerous bacteria and viruses are becoming resistant to commonly prescribed antibiotics. Even the superstars of the antibiotic world, such as penicillin, are often subverted and rendered helpless by some diseases that have developed an antibiotic resistance.

However, a University of California, San Diego bioengineering professor and his research group are now outsmarting these hardy organisms using a new scientific concept called "genetic circuits" computer simulations that describe how gene products (proteins, such as enzymes) interact to perform specific cellular functions. The research results were just published in a June, 1999 issue of The Journal of Biological Chemistry. The article describes the metabolic properties of Haemophilus influenzae Rd, a common human pathogen that causes respiratory infections and bacterial meningitis.

In computer experiments, his research group also used a genetic circuit approach to predict how E. coli mutants behave and projected the use of these models as a basis to develop new antibiotics. His predictions were 90 percent correct.

Dr.Bernhard Palsson, professor of bioengineering at the Irwin and Joan Jacobs School of Engineering, says that genetic circuits would take the Human Genome Project to the next logical step. As a secondary initiative of the Human Genome Project, scientists have completely mapped the entire genome sequence of at least 19 microorganisms, including yeast, E. coli (a disease-causing microorganism) and Helicobacter pylori (a cause of gastric ulcers), with dozens more to soon follow.

Scientists have also begun identifying specific genes, their products, and functions in these organisms. The mapping or "sequencing" of organisms means their DNA has been completely traced. This provides the necessary information to build models of their genetic circuits. If those 19 microorganisms had not been first mapped, the genetic circuits approach could not be implemented. Some pharmaceutical companies have used supercomputers to model individual molecules - there are millions in a cell - (micro), but the genetic circuit approach is a modeling of the systems within the cell (macro).

Some of the other dreaded organisms that have been sequenced include those involved in the onset of Lyme disease, tuberculosis, syphilis and gonorrhea. When you get sick from a bacterium such as E. coli, the bacterium produces toxins that the body reacts to with inflammatory responses seen as symptoms of the illness. An antibiotic stops the growth, or blocks the advancement path, of the bacterium and allows the bodyís natural defenses to overcome and kill the bacterium.

The genomics (study of genes) revolution, Palsson said, has provided us with extensive amounts of information on the DNA, RNA and protein levels in specific organisms.

"The Human Genome Project gives us a complete spare parts catalog-like you might have for your car. However, to understand how the car engine runs or the brakes work, you need to know how all of the parts work together," said Palsson. "Every cellular function is a system requiring the overlapping interaction of dozens of gene products. To truly understand how cells behave, we will have to identify the pathways through which gene products communicate and create computer simulations of this circuitry."

One of the first applications for genetic circuits, Palsson predicts, will be development of drugs designed to fight antibiotic-resistant strains of bacteria and viruses. The metabolic, or basic life source, reaction network in the cells of a given bacteria can now be reconstructed from information learned from its genome sequence. This network of reactions is the means by which bacteria generate the building blocks of the cell. With this knowledge, the network can be probed to find critical links that when removed render the network inoperable.

"We can create a computer model that can simulate the genetic circuit for metabolism and growth in a disease-causing microorganism. We can then systematically remove various gene products in this circuit and identify the weak spots in their metabolism-genes that are important to the survival of the organism. These would be the targets for new antibiotic therapy," said Palsson.

"The metabolic pathways of an organism, such as bacteria, are similar to traffic patterns. If a side road is shut down, drivers will find an alternative route, and continue on to work. If a major freeway is shut down, it could literally stall the morning commute," Palsson said. "The goal would be to identify all of the major genes and disable them simultaneously with a multiple hit, cocktail-type antibiotic, so that the bacteria cannot grow and mutate to evolve an antibiotic resistance."

Treatments for cancer and diabetes are on the horizon using genetic circuits as a guide to help find a complete understanding of cell functions and malfunctions. However, Palsson cautions, given the time it takes for clinical trials in the development of new antibiotics, it could be five to eight years before treatments are in hand.

Scientists had already uncovered the gene products that are involved in E. coli metabolism, a well-studied bacteria. When Palsson tested his ideas with E. coli, his group determined the limitations and functions of each gene in the context of the entire metabolic network of E. coli.

They then removed single genes from his computer model-just as the genes would be disabled with drug therapy, and the model rerouted the circuit for E. coli metabolism exactly the same way that E. coli is known to mutate in real life. The model was accurate in nine out of every 10 simulations. Palsson is now testing his theories with other disease-causing microorganisms such as influenza and strains of Helicobacter.

"For decades, the source of genomic DNA sequences came from independent laboratories, whose studies focused mainly on the functional aspects of a particular gene producing a sequence only as a secondary result to their main research objectives," Palsson said. "Only within the past decade with the development of automated sequencing technologies have genome sequencing projects been initiated in which the primary objective is to determine DNA sequences independently of gene function," he added.

"Bioengineering today is in about the same stage of development as the electroengineering discipline was in about the late 1950s," Palsson said. "Those were the analog days of vacuum tubes, with microchip circuitry and the digital revolution only on the horizon. We are going to see a tremendous increase in knowledge in the area of genetic circuitry in the next 40 to 50 years."

Palsson pointed out that on July 28, 1995, only five years after the Human Genome Project outlined its initiatives, the first complete genome sequence of an organism (Haemophilus influenzae) was published in Science magazine.

The concept of genetic circuits was created by Palsson in 1996 during a solo brainstorming session. "I had been in Denmark on a Fulbright Fellowship and I had a period of time before I came to UC San Diego," Palsson said. "I began to plan my academic life and look at what had transpired in my own research and in my field. Two major things came together for me. One was my 15 years of modeling metabolic activity and the other was the development of genomics. Out of these combined elements, my theory developed. Some people scoffed at it and said it was way too futuristic, but I was convinced that it could be done."

Palsson delivered a lecture about his theory, and the editor of Nature Biotechnology magazine-a very prestigious publication in the biological world-invited Palsson to write a commentary about it in January 1997, and that was the first mention of genetic circuits. Since then, interest has grown tremendously in Palssonís concepts.

Palsson sees the emergence of a new field of study named "Phenomics." (The "pheno" comes from phenotype, or "an observable trait". The "nomics" comes from genomics, the science of studying genes.)

"Given the fact that the vast majority of cellular functions are multigeneic in nature and that each gene product has a physical-chemical function, Phenomics will be based on the study of integrated cellular systems and basic physical-chemical laws," Palsson said. "This field of study will combine the biological, physical-chemical and systems sciences in ways never seen before. I have suggested that the concept of a genetic circuit will become an important new biological paradigm, and will become a fundamental component in our treatment of the relationship between genetics and physiology."

Genetic circuits may be the key to locking forever the Pandoraís Box of dangerous bacteria and viruses that have forever plagued mankind.


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