Key to understanding biological evolution is an important, but elusive, connection, known as the genotype-phenotype relationship, which translates the survival of entire organisms into microscopic selection for particular advantageous genes, or protein sequences. The study of Shakhnovich et al establishes such connections by postulating that the death rate of an organism is determined by the stability of the least stable of their proteins.
The simulation of the model proceeds via random mutations, gene duplication, organism births via replication, and organism deaths.
The authors find that survival of the population is possible only after a Big Bang when a very small number of advantageous protein structures is suddenly discovered and exponential growth of the population ensues. The subsequent evolution of the Protein Universe occurs as an expansion of this small set of proteins through a duplication and divergence process that accompanies discovery of new proteins. The model resolves one of the key mysteries of molecular evolution , the origin of highly uneven distribution of fold family and gene family sizes in the Protein Universe. It quantitatively reproduces these distributions pointing out their origin in biased post ,Big Bang evolutionary dynamics of discovery of new proteins. The number of genes in the evolving organisms depends on the mutation rate, demonstrating the intricate relationship between macroscopic properties of organisms , their genome sizes , and microscopic properties , stabilities , of their proteins.
The results of the study suggest a plausible comprehensive scenario of emergence and growth of the Protein Universe in early biological evolution.
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According to Dr. Monga, these results suggest that PDGFR offers an important new therapeutic target for the treatment of HCC.
"We are very excited because this is the first targeted therapy for liver cancer. Other therapies have some modest benefits, but no one knows exactly how they work. We now have identified a pathway that appears to be overly active in more than 70 percent of the cancers we examined and, when targeted, leads to significant reduction in tumor cell proliferation and survival," said Dr. Monga.
More importantly, targeting the PDGFR pathway in liver cancer cells does not appear to affect normal liver cells, making the treatment relatively non-toxic. "Normally, regenerating liver cells are not exclusively dependent on this pathway, and it is not overly active in other types of cells. So this monoclonal antibody is a highly targeted treatment for this disease," he added.
Furthermore, because high expression of PDGFR has been detected in a variety of tumors, such as skin cancer, brain tumors, gastrointestinal tumors, prostate tumors, ovarian cancer and leukemia, Dr. Monga believes these findings could have much broader applications.
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