A computational model of metabolism in human tissues

The model developed at Tel Aviv University and with the participation of American researchers allows the metabolic aspect of ten healthy tissues, including the heart, to be monitored * Prof. Eitan Rupin from Tel Aviv University who headed the research published in Nature Biotechnology: it will be possible to develop models for any disease and try drugs in simulation

A computer model developed by a team of researchers led by Prof. Eitan Rupin from Tel Aviv University, will be able to help simulate the metabolism in different tissues of the human body, for the purpose of researching many diseases. This is according to an article published today in the journal Nature Biotechnology.

In addition to Rupin, Tomer Shlomi participated in the research, which was his doctoral thesis, Moran Kabili, as well as two researchers from the University of California at San Diego - Marcus Hergard and Bernard Pelson, members of the group that published a study of which the current model is a continuation and elaboration.

The study reveals the central role that different control processes have in determining the tissue metabolic pattern. The model successfully predicts the tissue association of many metabolic processes, genes and metabolites. A computational basis was therefore laid down that will enable in the future a large-scale study of many metabolic disorders and diseases in various tissues, including diseases such as diabetes and obesity, genetic metabolic diseases, neurodegenerative diseases such as Alzheimer's, and characteristic changes in metabolism that occur in malignant diseases.

In a conversation with the Hidan website, Prof. Rupin explains that the holy grail of computational biology is building computer models of biological systems that we are interested in. "The vision is that if we have a good description of such biological systems inside the computer we can do simulation experiments instead of animals or human cultures, or in drug development processes."

"However, we are far from developing a simulation for a living cell, because there are many aspects to the activity of even the simplest cell - even yeast cells. Therefore, our task is more modest - measuring one of these parameters, admittedly one of the main ones - metabolism, and building a reliable model of it."

Where did the idea come from?

As usual in science we sit on the shoulders of giants. About a year and a half ago, an article was published in PNAS by an American group that is one of the leaders in the world in the computational research of metabolism that described the first model of metabolism in humans. It was an amazing job in which they invested many years and a lot of energy. They cite in the study no less than 1,500 articles that they read and reviewed to build the model and they conducted initial validity (validation) tests for it. But the model they developed is a generic model, it does not describe the metabolism in a specific tissue. Man is a multicellular and multitissue creature. What we have done in the current work is to develop, based on the infrastructure of their work, specific models for metabolism in humans for specific tissues. Among other things, the brain, the heart, the liver, the kidney, etc.

"After we developed these specific models we validated them by gathering from the literature all the knowledge available today about the metabolism that occurs specifically in these tissues and we showed that the predictions of the model really correspond to the current knowledge. In addition, we have provided new predictions that go beyond the currently known knowledge and characterize the metabolic state of healthy body tissues."

Gene expression in diseases

"Our method allows, given certain knowledge about gene expression, to build such a description for any tissue we want. We actually developed a simulation for ten tissues, but we presented a basic method that makes it possible to do this given gene expression information for each tissue. In addition to the healthy genes, the model allows us to describe and study the changes in the metabolic state in various diseases. Many diseases have consequences in the field of metabolism, the most prominent being obesity and diabetes - from the Western world, and there are also over 300 genetic diseases, although rare, that occur as a result of a defect in the gene responsible for metabolism, for example, phenylketonuria, or Paul's disease in Eastern Jews."

"Beyond these diseases there are also other diseases in which metabolism plays a central role - first and foremost, neurodegenerative diseases such as Alzheimer's and Parkinson's where cell death occurs, but what causes cell death is a process called apoptosis, one of the main triggers of which are disturbances in mitochondrial metabolism. We also learned about metabolic changes that occur in malignant cells. Therefore, the metabolic description that we give to the various tissues contains within it the possibility of trying to investigate and better understand in a computational way what happens in these diseases from a metabolic point of view."

Credit to researchers

"You have to give credit to the two students - Tomer Shlomi and Moran Kabili who did the bulk of the work." says Prof. Rupin. "Shlomi is finishing his doctoral thesis at Tel Aviv University and got an immediate position as a faculty member at the Technion, and Kavili, who finished her two degrees in the unique bioinformatics track at Tel Aviv University, finished her master's and went to do a doctorate at Harvard in the Department of Systems Biology. The other partners Marcus Hergart and Bernard Pelson are American partners from the world's leading group in the field of computational metabolism, and she is the one who developed the basic human model, from which we started, so you can see the interdisciplinarity required for this type of research."

And what are the plans for the future?

Prof. Rupin concludes: "The model we developed is only a starting point. This is a close model that demands continued improvement and accuracy and much more work is needed. This is basic science and a lot more work is required, and it continues all the time both by us and by other groups in the world."