Biomedical Research

Fundación’s biomedical research encompasses such diverse subjects such as cancer, immunology, virology, neuroscience, cell biology among others. Some of our research is conducted collaboratively with universities and companies. Fundación Ciencia para la Vida is conducting research in the following areas:

• Novel RNA technology to treat and diagnose Cancer (more)
• Hantavirus infections (more)
• Unfolded Protein Response and autophagy (more)
• Dendritic cell biology and lymphocyte homing (more)
• Molecular basis of tolerance, autoimmunity and Lupus (more)
• Molecular basis of immunosuppression and transplant (more)
• Analysis of the post-translational modifications in histones (more)
• Role of neurotransmitters on the regulation of immune response (more)

 Novel RNA technology to treat and diagnose Cancer
Fundacion in conjunction with Chile's largest biotechnology Company, GrupoBios, is developing a new family of highly selective anticancer molecules, based on antisense oligonucleotides and interference RNA. A novel family of non-coding RNAs of mitochondrial origin has been discovered and characterize as new cancer markers.
These RNAs are present in both, sense and antisense copies. Normal proliferating cells express both copies. Normal resting cells do not express these RNAs at all; but in cancer cells the sense RNA is normally expressed while the antisense RNA is strongly down regulated. This cellular “phenotype” has been confirmed in dozens of cancer cell lines and hundreds of tumor biopsies, lending itself as a potential new Cancer marker.

A new diagnostic method to determine circulating tumor cells in urine samples is being developed to diagnose bladder and prostate cancer. The extension of this research could help detect circulating tumor cells after a surgical or chemical/radiological treatment. Animal studies are being carried out in collaboration with Dr. Marc Shuman at the Comprehensive Cancer Center of the University of California, San Francisco. For further information please contact us on the following address. (back to top)

 Hantavirus infections
Hantaviruses are pathogens of worldwide public health concern causing severe hemorrhagic fevers with renal or pulmonary syndromes in humans. In Chile and Argentina the fatality rate is close to 30% and currently no effective treatment is available.
In collaboration with Chile’s Instituto de Salud Pública (Public Health Institute), researchers at Fundacion Ciencia para la Vida have sequenced the viral genome of the Chilean hantavirus (Andes species) and have obtained recombinant antigens in line with the development of products for the diagnosis, prevention and treatment of this infection.

Fundacion´s research is further focused on the molecular characterization of the mechanism by which hantaviruses enter into human cells. The fusion active protein (Gc) of hantaviruses has been identified and characterized.  Gc is responsible for the fusion process between the viral envelope membrane and cellular membranes through which the virus injects its nucleocapsids into the cytoplasm. 
Also a 3D molecular model structure of Gc was derived in collaboration with the Centro de Bioinformatica of the Universidad Catolica. This structure together with studies of the Gc fusion peptide support the classification of Gc as a class II virus fusion protein. For further information please contact us on the following address.(back to top)

Unfolded Protein Response and autophagy 
For secreted and membrane proteins to transit through the secretory pathway requires that they first complete folding in the Endoplasmic Reticulum (ER). The ER therefore constitutes a protein-folding factory that imposes exquisite quality control on its products, ensuring that only properly assembled and functional proteins are delivered to their ultimate destinations.

The load of proteins deposited into the ER varies between cell types and during the life of a cell. Cells frequently encounter situations that cause the protein folding demand to overwhelm the ER's folding capacity, resulting in ER stress. To cope with and adapt to ER stress, an intracellular ER-to-nucleus signal transduction pathway evolved to dynamically match the ER's protein folding capacity to need.

This pathway, called the unfolded protein response (UPR), increases the amount of ER membrane and its components, including chaperones and protein modifying enzymes needed to fold proteins. The UPR also decreases translation and loading of proteins into the ER and enhances the targeting of unfolded proteins in the ER for degradation. To this end, unsalvageable unfolded polypeptides are returned to the cytosol to be degraded by the proteasome. If a homeostatic balance is not estalished after inducing the UPR, cells commit apoptosis.

Thus cells at risk of displaying malfunctioning proteins on their surface are actively eliminated from an organism. An alternative pathway that targets proteins for degradation is autophagy. Autophagy describes a collection of pathways by which sections of the cytoplasm, including its organelles, can become sequestered into membrane-bounded compartments that then fuse with the vacuole (or lysosomes), where their content is degraded by acid hydrolases. In this way, whole organelles can be degraded, regardless of their size or the folding state of their constituent proteins. Many of the components that mediate autophagy have been identified and
extensively characterized.

Fundacion's research focuses in the connection between the UPR and autophagy, the mechanisms used by the cell to activate autophagy, and the role of these processes for cell viability, for example, during the progression of diseases where protein aggregation is an essential issue. (back to top)

Immunology Research

Fundación´s Immunology Team carries out research in three main areas:

• Dendritic cell biology and lymphocyte homing
  
• Molecular basis of tolerance, autoimmunity and Lupus
  
• Molecular basis of immunosuppression and transplant
  

Dendritic cells are located at the main sites of pathogen entry and are the key sentinels of the immune system, signaling T lymphocytes about the perils of infection. Our research team carries out studies on several aspects related to the molecular and cellular mechanisms regulating dendritic cell biology and T cell migration. Our group was the first in recognize the central role that dendritic cells play in instructing T lymphocytes as to the site of pathogen entry. This research is done in collaboration with Dr. María Rosa Bono and a group of biochemists and graduate students from the Faculty of Sciences at the University of Chile.

Related to this research we are also investigating on the cellular basis of Lupus, an autoimmune disease affecting mainly young women. Using an animal model for the human disease, our studies have established that the lymphoid microenvironment is modified during disease development, shaping the way dendritic cells determine pathogenesis.

Also, in collaboration with a team of physicians headed by Dr. Alberto Fierro from Clínica Las Condes we are involved on a project in clinical immunology in the area of organ transplants. We have developed a new and efficient protocol for the generation of regulatory T lymphocytes, a group of cells involved in down-regulating the immune response. We are using these cells to promote organ acceptance in transplanted animals.

On a different subject, we are also investigating the immune system of salmon and the model zebrafish. The purpose of this research is to gain inside on the mechanisms regulating the immune response of salmon, one of the main pisciculture species of commercial value in Chile. For further information please contact us on the following address. (back to top)

 Analysis of the post-translational modifications in histones

DNA in eukaryotes is compacted into chromatin, of which the basic unit, the nucleosome, is composed of two copies of each of the four histones H2A, H2B, H3, and H4, wrapped by 147 base pairs of DNA. Chromatin not only compacts the DNA but, given its dynamic nature, plays an important role in the regulation of gene expression. Different machineries keep chromatin in a dynamic state, including chromatin remodeling factors, histone variants, and histone modifying enzymes that confer post-translational modifications (PTMs). Histones, particularly their N-terminal tail, are among the most highly modified proteins. PTMs, including acetylation and methylation, occur in specific residues. Based on the effect that PTMs have on transcription, modifications can be divided into two classes: “active modifications”, such as lysine hyperacetylation, methylation of lysine 4 and 36 of histone H3 (H3K4me and H3K36me); and “repressed modifications”, such as hypoacetylated lysines, H3K9me, H4K20. Particular histone modifications and defined combinations of PTMs (PTM patterns) can act as docking sites for specific factors to assist in the formation of define chromatin domains. For example, methylated H3K9 promotes the formation of heterochromatin by interaction with heterochromatin protein 1 (HP1).

Histone variants are another mechanism to keep chromatin dynamic. They are the products of distinct genes, which share amino acid sequence with the major class of histones (replicative histones). In humans, the histone H3 variants H3.1 and H3.3 differ at five amino acid positions. In spite of this, H3.1 interacts exclusively with the histone chaperone CAF-1 and H3.3 with the chaperone HIRA. Interestingly, these two chaperones support replication-coupled and replication-independent chromatin assembly, respectively. Epitope-tagged versions of H3.3 have shown that H3.3 associates with transcriptionally active chromatin both at promoter and in the transcribed region of genes. Consistently, H3.3 is enriched in PTMs associated with transcriptional activation, whereas H3.1 is enriched in repressive marks.
                                                                                                                                                            An emerging view is that histone PTMs and histone variants not only regulate gene expression, but are crucial in determining epigenetic states. These are heritable changes in gene function unrelated to changes in the DNA sequence. Therefore, a crucial question in this field is how and when PTMs and PTM patterns are established. In order to address this issue we analyzed PTMs present in the human H3.1 and H3.3 variants isolated before and after chromatin assembly (non-nucleosomal and nucleosomal H3, respectively). We showed that methylation PTM patterns on the histone variants H3.1 and H3.3 are mainly established after histones are incorporated into the chromatin. The exception of this is H3K9 methylation, which is the only lysine residue methylated in the non-nucleosomal histone H3. However, it remains crucial to understand what is the role of this preexisting modification pattern and how it is established. The goal of our team is to investigate what is the role of the non-nucleosomal H3.1 and H3.3 PTMs and how non-nucleosomal H3.1 and H3.3 PTM patterns are established. We anticipate that the investigation of the establishment of the non-nucleosomal H3.1 and H3.3 PTM patterns will help us to have a better understanding of the role of histone variants and their PTMs in the regulation of gene expression. For further information please contact us on the following address. (back to top)

 Role of neurotransmitters on the regulation of immune response

The immune system has an extraordinary task: to recognize and eliminate foreign antigens without causing serious damage to self-tissues. Such specificity for recognising foreign antigens from self-constituents is carried out by a sophisticated system involving T cells and dendritic cells (DCs). T cells are the central players in the immune response. They recognise foreign antigens and regulate function of several immune system cells, thus orchestrating efficient elimination of invading pathogens and neoplasia. On the other hand, DCs play a pivotal role of presenting antigens to naïve T cells, directing and regulating the activation and further differentiation of T cells. Thus, T cells as well as DCs constitute two key players in the immune response. Consequently, the deregulation of the function of these cells may result in an imbalanced immune response, thus allowing the development of autoimmunity, tumor growth or exacerbated susceptibility to infections.
                                                                                                                                                          Emerging evidence has suggested the existence of regulatory communications between the nervous system and the immune system.  However the mechanisms operating in such communication networks remain unknown. The main task of our Neuroimmunology group is to understand mechanisms that promote communication between the immune system and the nervous system. Our research focuses on understanding mechanisms that allow the nervous system to regulate the T-cell mediated immune response.
                                                                                                                                                          Throughout the last decade an emerging number of studies have shown that, in addition to neurons, immune system cells can also be regulated by neurotransmitters. The identification of these receptors on immune system cells suggests that neurotransmitters may play a role in the regulation of the immune response and that an imbalance of the activation of these receptors could be involved in the development of immune-related diseases. Moreover, this fact implies that different physiological or pathological states of the nervous system could be involved in the regulation of immune response. Furthermore, expression of neurotransmitter receptors on leukocytes and expression of cytokine receptors on cells from nervous system suggest possible bidirectional communication networks between the immune system and the nervous system. In addition, in recent years, many studies have suggested that some immune cells may synthesise, capture and store neurotransmitters which are released under determined conditions. This property would allow these cells to establish autocrine or paracrine communications with leukocytes and with nervous cells.
                                                                                                                                                           The primary aim of our research is to determine how some neurotransmitter-mediated pathways from the nervous (inter-systemic) or immune (intra-systemic) system are capable of regulating the T-cell function and the DCs physiology in vivo. The potential findings could be highly relevant in clinical applications, such as in the rational design and development of immunotherapies for treatment of disorders involving an imbalance of immune response, for instance cancer or autoimmunity. For further information please contact us on the following address.(back to top)

 If you want know more about our research on the following link