Bernhard Palsson and his team of bioengineering researchers at the University of California have spent over a year looking through 50 years of research and text to compile the most comprehensive list of metabolic pathways to date. From that data, they’ve created a ‘virtual model’ that may allow scientists to study how medications may affect the body.
This first-of-its-kind metabolic network builds on the sequencing of the human genome and contains more than 3,300 known human biochemical transformations that have been documented during 50 years of research worldwide.
In a report in the Proceedings of the National Academy of Sciences (PNAS) made available on the journal’s website on Jan. 29, the UCSD researchers led by Bernhard Palsson, a professor of bioengineering in the Jacobs School of Engineering, unveiled the BiGG (biochemically, genetically, and genomically structured) database as the end product of this phase of the research project.
… the UCSD researchers conducted 288 simulations, including the synthesis of testosterone and estrogen, as well as the metabolism of dietary fat. In every case, the behavior of the model matched the published performance of human cells in defined conditions.
Researchers can use the computationally based database to quickly discover the effects on a given cell type of changing the performance of any of the 3,300 known human metabolic reactions operating in that cell. The tool is designed to help scientists explore hundreds of human disorders in the metabolism of amino acids, carbohydrates, lipids, minerals, and other molecules. It also is intended to be used in the future to study metabolic variations between people as a way to individually tailor diet for weight control…
More than two dozen biochemical reactions in human cells are needed to make cholesterol. Cholesterol-lowering drugs called statins affect just one of those reactions, reducing the synthesis of cholesterol as if they were pinching a garden hose, slowing the flow of cholesterol through it. However, metabolic pathways are actually labyrinths of interconnected garden hoses with complicated flow patterns.
“Pinching off one part of the labyrinth can have a good effect, but it can also have unexpected consequences, or even no effect because of redundancy built into metabolic systems,” Palsson said. “The new tool we’ve created allows scientists to tinker with a virtual metabolic system in ways that were, until now, impossible, and to test the modeling predictions in real cells.”
Each type of cell in the human body utilizes only a fraction of all 3,300 metabolic reactions, and scientists can create in silico any type of cell, from a heart cell to a red blood cell, with its particular complement of metabolic enzymes, and adjust their genetic or other properties to compute the cell’s behavior.
“We can analyze abnormal metabolism at the root cause of diseases such as hemolytic anemia, which can result from a deficiency in metabolic reactions,” said Neema Jamshidi, an MD/Ph. D. student at UCSD and co-author of the paper. “We can study both the causes and consequences of this and other diseases, which may lead to novel insights about how new drugs might be designed to treat them.”