The Scripps Research Institute
California

Decoding and translating and genetic information to stop disease

Can cancer be cured by delving deeper into the subjects of biology and molecular biology? Quite possibly.
By examining life at its most minute levels, basic research scientists are decoding the structure and function of the building blocks of life, DNA, RNA, and proteins. They study the intricate mechanisms of how cell molecules are able to use the genetic codes in DNA and RNA to build all proteins in a cell-a process called translation. Armed with this fundamental knowledge, scientists hope to correct errors which occur when cells form and function - and to have the capability to intervene in diseases, such as cancer.

NFCR Fellow Expertise

Dr. Schimmel is a member of the National Academy of Sciences and is a world renowned expert on cell molecular biology, biochemistry and enzymology or the study of enzymes. He has dedicated his 40+-year career to the decoding of genetic information in translation, protein-RNA recognition, and the connections between translation and cell signaling. Much of his research has focused upon the enzyme, tRNA synthetase, which catalyzes the reaction between the genetic code in RNA and amino acids or the individual components of proteins. His research on tRNA synthetases has suggested, and is believed by many, to be among the first enzymes to arise on the planet in the early stages of the evolution of life.

Dr. Schimmel is one of the few scientists to study both nucleic acids (DNA and RNA) and proteins. His laboratory was one of the first to identify the "operational RNA code"-another code in an RNA molecule that is different from the usual "genetic code" for protein building. It is widely regarded that the "operational RNA code" possibly was the original code of life and could give rise to the "genetic code" and early systems of protein synthesis.

NFCR Research Overview

With financial assistance from the National Foundation for Cancer Research, Dr. Schimmel is investigating the components in cells that are responsible for protein synthesis and the genetic code. By understanding how these components interact with one another, Dr. Schimmel hopes to learn how they might be used to turn off a variety of disease processes, including infectious microorganisms, viruses, and cancers.

NFCR Research Findings

His team at Scripps Research Institute recently discovered that human cells use three different quality control checkpoints to produce proteins-the key molecules that keep our bodies in their normal, healthy state-free of defects. Two of checkpoints are carried out by the tRNA synthetases and the third is from a cell molecule similar to part of tRNA synthetase. The findings explain, for the first time, how these checkpoints identify and correct the errors occurring during protein production. The connection between errors in protein translation - an important step in protein production - and cancer -can now be fully investigated because of this new knowledge on quality control checkpoints.

In science, one discovery opens another door and Dr. Schimmel has opened another door from this discovery of the quality control processes by tRNA synthetases to produce defect-free proteins. Dr. Schimmel proposes a new way how cancers develop as we age. He proposes that if tRNA synthetases become defective themselves, then they are unable to correct the errors occurring in proteins as they are constructed. These errors in protein production accumulate, or occur more often, as a cell ages, and some defective proteins eventually can lead to the activation of genes that cause cancer. His team is testing this idea using their unique tumor model system in which they can introduce genes for tRNA synthetases that are defective in their normal editing function. The model allows scientists to learn how the construction and accumulation of proteins with errors, over time, relates to cancer initiation in cells. Verification of Dr. Schimmel's idea-that defective tRNA synthetases can initiate cancer-may lead to the development of novel strategies for treating and preventing cancer in aging individuals.

Dr. Schimmel and his colleague at The Scripps Research Institute, Xiang Lei Yang, Ph.D., are seeking to understand why human amino acyl tRNA synthetases, have distinct additional vital activities, that are involved in pathways relevant to treating cancer and other diseases. The scientists have made a landmark discovery of how one tRNA synthetase inhibits blood vessel formation - also called anti-angiogenesis. By inhibiting the formation of a tumor's blood vessels, the tumor is starved of the vital nutrients it needs to grow. The discovery has fueled the development of new anti-angiogenesis approaches for the treatment of cancer that depends on new vessel formation.

Recently, the team has shown that another tRNA synthetase has robust activity in slowing and stopping melanoma growth in tumor models. In fact, when the enzyme is given with chemotherapy, tumor suppression activity is greater than either agent alone. With continued research, this tRNA synthetase may provide the basis for a new therapy against malignant melanoma.

Impact on Cancer Prevention, Treatment, or Cure

Dr. Schimmel's detailed understanding of how RNA directs protein synthesis provides dramatic clues about the origin of life. Just as important, his work has shed light on how genetic mistakes occur and how new drugs might be developed that could correct these mistakes. Cellular defects can be corrected by binding drugs to RNA targets. Microorganisms that cause infections or viruses can be eliminated by directing drugs to precise targets. Tumor cells can be eliminated by blocking specific proteins, while sparing healthy cells. The ancient enzymes, tRNA synthetases, may be a modern way to treat cancer as this research reveals that these proteins have other cellular functions relevant to cancer. The Schimmel team's ground-breaking work has the potential to extend and improve life for all of us.