Wednesday, October 5, 2011

Human genome project: What's Next?

The Human Immunopeptidome Project

Technion researchers are  proposing the launch of an international research project to define in detail the repertoire of immune peptides presented by human cells and to use these peptide fingerprints to diagnose diseases and personalize treatments: The Human Immunopeptidome Project

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Professor Arie Admon
During recent years, the Human Genome Project has fulfilled many of its original goals. It has created huge database of genetic information, incuding the nucleotide sequences of entire genomes of many people. This knowledge has been translated to useful medical and biological discoveries and applications, including the determination of the amino acids sequences of all human proteins.

Lately, as the Human Genome Projects completes its most demanding stage,  scientists are asking themselves “what next?” It is clear that obtaining the sequences of numerous genomes is not the end of the process. The scientific community wants to know which genes are expressed and translated into proteins, in which cells and tissues and at what stage of development. It is essential to find out the relative levels of the different protein in each cell type, their unique patterns of posttranslational modifications, their three dimensional structures and how these structures affect their cellular functions. Since each of the proteins have different lifetimes until they are degraded in the cells, it is important to find out what factors sending these proteins for degradation. Knowing all these important features of genes and proteins is also important for medicine. When cells become infected with viruses or bacteria or become cancerous, the patterns of gene expression and protein function are altered significantly. Better knowledge of the structure and function relationship of the different cellular and pathogens proteins are extremely important for drug design and vaccine development.



A top research field benefiting from the discoveries stemming out of the Human Genome Project relates to development of new technologies for better diagnosis of disease and personalized medicine, most importantly for cancer. Indeed, last year a team of Technion researchers have developed a new approach for disease diagnosis based on a simple blood test, published in the prestigious journal, Proceedings of the National Academy of Science (PNAS)

The new method was developed in the laboratory of Professor Arie Admon in the Faculty of Biology at the Technion by Dr. Michal Bassani-Sternberg as part of her Ph.D. thesis. As a continuation of this research direction Professor Admon and Dr. Bassani-Sternberg now propos to launch an international research project to come to a better understanding of human immunology; to diagnose diseases and to develop even better immunotherapies for infectious diseases, cancer and autoimmunity. 

The new approach for disease diagnosis developed by Dr. Bassani-Sternberg and Prof. Admon is based on the fact that most cells in the human body (except red blood cells) ‘present’ at their surface diverse repertoires of peptides as a way of informing the immune system of the health-state of the cells. The immune system of all organisms needs to know at every moment how healthy the cells are, in order to prevent the spread of the disease, especially when cells are infected with pathogens. One of the most effective ways the immune system find out about infection of cells with pathogens is through this presentation of peptides at the cell surface by the Human Leukocyte Antigen (HLA) protein. The peptides presented by the HLA protein at the cells’ surface are short (8-11 amino acids long) peptides which are derived from degradation of most cellular proteins. When cells become infected with pathogens or become cancerous, they degrade also some the pathogens’ proteins or cancer related proteins. The degradation products of these disease related proteins are also sent for presentation at the cells’ surface by the HLA molecules. Presentation of peptides derived from disease related proteins at the cells’ surface induces a strong reaction in a special group of white blood cells, called T lymphocytes, which kill the infected cells while alerting the immune system, multiply and proceed to kill more of the infected cells. This way, the immune system stops the invasion of pathogens before the spread and cause irreversible damage to the body.

During the last year new instruments and technologies facilitate the identification and the quantification of thousands of different proteins present in the cells and tissues. The same tools and technologies are also used for analysis of the repertoires of peptides presented by the HLA proteins at the cells’ surface. Analysis of these peptide repertoires, nicknamed ‘the immunopeptidomes’, and comparing between those presented on normal versus diseased cells allows the identification of those peptides presented only by diseased cells. The information obtained by analysis of the thousands of different peptides composing these immunopeptidomes facilitates the development of better vaccines for both infectious diseases and cancer. Furthermore, familiarity with these immunopeptidomes provides a rich source of information about the ways cells function and respond to diseases and stimuli.

Admon and Bassani-Sternberg propose that the time is ripe for the launching of this new Human Immunopeptidome Project, which will focus on the identification of the entire repertoires of peptides presented by all the different types of cells, both in health and disease. Since the HLA protein is somewhat different between people (it is the most polymorphic gene among the different human genes with more than 3000 known alleles) and each of its subtypes presents a different set of peptides by the cells, the proposed immunopeptidome project will aim to define also the unique characters of peptides presented by each of these subtypes of HLA molecules. Recent developments in mass spectrometry  are powerful enough to allow identification of tens of thousands of different peptides as needed for such project.

The proposed Human Immunopeptidome project is ambitious and can be achieved only through international collaboration.  Yet, it is clear that the potential outcome of such project is huge and its contribution to medicine is eminent. If this project will be launched, the data generated by it will become publically available to all scientists and medical doctors, most likely through the internet. Using this data, researches and doctors will be able to develop immunotherapies for infectious diseases, cancer and maybe even for autoimmune diseases.

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