Molecular biology highlighted at FAPESP Week Montevideo

Researchers from Uruguay, Paraguay and Brazil presented results of research on cellular and bacterial signaling and virus characterization.

By Heitor Shimizu, in Montevideo  |  Agência FAPESP – Hugo Aguirre Armelin, coordinator of the Center for Research on Toxins, Immune Response & Cell Signaling (CeTICS), spoke to fellow-researchers at FAPESP Week Montevideo about ongoing activities at the institution, which is attached to Butantan Institute in Brazil and is one of the Research, Innovation & Dissemination Centers (RIDCs) funded by FAPESP.

The event took place on November 17-18 in the Uruguayan capital and was organized by FAPESP in collaboration with the Montevideo Group Association of Universities (AUGM) and Uruguay’s University of the Republic (UDELAR).

The interdisciplinary group led by Armelin is working on projects such as modeling the cycle of Ras-GTPases, which are molecular on/off switches that control various pathways in the molecular cell signaling network.

“In recent decades the immense volume of data generated by such fields as genomics and proteomics has led to the production of intricate static maps of molecular cell signaling networks. But these maps are insufficient to predict cellular responses to hormones, growth factors, cytokines, drugs or toxins, for example,” Armelin said.

“As a result, one of the major challenges for biology today is to convert static maps into dynamic models based on quantitative and functionally predictive data. Models that enable us to discover molecular signaling pathways linked to complex phenotypic alterations.” Armelin was Full Professor of Biochemistry at the University of São Paulo from 1985 until his retirement in 2009.

Researchers in molecular cell biology and computational biology at CeTICS have built dynamic computational models of Ras-GTPases. Ras is a family of related proteins expressed in all animal cell lineages and organs. All Ras protein family members belong to a class of proteins called GTPases (molecular switches), and are involved in transmitting signals within cells (transduction).

Armelin spoke at the Montevideo meeting about the K-Ras GTPase kinetic model developed by CeTICS. The model was experimentally validated using the Y1 mouse adrenal tumor cell line dependent on K-Ras gene amplification.

“This K-Ras GTPase kinetic model is a small computational module but it enables us to make promising predictions of molecular pathways that control complex cellular phenotypic transitions,” he said. “We’re investigating whether and to what extent these findings are transferable to the molecular signaling networks of human cells.”

Bacterial signaling

How bacteria perceive signals in their vicinity was the subject of a presentation by Alejandro Buschiazzo from Montevideo’s Pasteur Institute. His research focuses on pathogenic bacteria of the genus Leptospira. These bacteria cause diseases that lower animal productivity and lead to herd losses, a major problem for Uruguay’s beef industry.

Buschiazzo’s group at Pasteur are exploring the molecular basis of protein functions from the standpoint of structural biology with the ultimate goal of developing more efficient vaccines against leptospirosis.

Structural biology is the study of the molecular structure and dynamics of biological macromolecules, especially proteins and nucleic acids Buschiazzo stressed that in the last 60 years this branch of molecular biology and biochemistry has made enormous contributions to the determination of the biochemical properties of a large number of proteins, many of which are involved in important biological and pathological processes.

“The vast amounts of data available lead us to pursue systemic approaches that are more integrative and cover a wide range of temporal and spatial resolution scales,” he said.

Using a combination of molecular biology, biochemistry, protein crystallography and computational tools, Buschiazzo’s group discovered the mechanism whereby bacterial proteins known as histidine kinases use a helical switch or specific response regulator to control catalysis and interaction with natural partners.

“We’ve learned a lot about signaling and regulation in bacteria,” he said. “Protein plasticity plays a key role in the biology of pathogens. Our challenge is to deepen our understanding of this and other processes in structural biology while evolving to integrative approaches. In fact, we’re working on this with colleagues in Brazil.”

In 2015, Buschiazzo and colleagues at the Uruguayan and French Pasteur Institutes as well as UDELAR published an article in the journal Science describing the X-ray crystal structure of the native bovine leukemia virus capsid protein. The capsid is the structure that encloses the nucleic acid of a virus. Bovine leukemia is a chronic contagious infectious disease that represents another major problem for beef cattle breeders.

In 2014, Buschiazzo was awarded the François Jacob Prize by Uruguay’s Pasteur Institute in recognition of his work in crystallography, comparative genomics of Leptospira and creation of a structural biology network in Latin America.

Cervical cancer

Laura Mendoza, a researcher at the Public Health Department of Paraguay’s Asunción National University, works mainly in molecular virology studying the molecular characterization of human papilloma virus (HPV) in populations at risk and different ethnic groups.

Mendoza earned a master’s degree from the University of São Paulo (USP) (with a scholarship from FAPESP) and a PhD from Uruguay’s University of the Republic. She also investigates HPV-based cervical cancer screening and ecological and epidemiological aspects of the arbovirus in Paraguay.

In her presentation to FAPESP Week Montevideo, Mendoza recalled that cervical cancer is the fourth most common type of cancer worldwide, with 85% of new cases occurring in developing countries. In Latin America, she added, tests based on detection of HPV have had a huge impact on early detection of cervical cancer, reducing the number of cases.

“Today the challenge is implementing programs organized on the basis of testing for HPV and screening only women who test positive for HPV so as to reduce the number of referrals for colposcopy and avoid possible overtreatment,” she said.

Among the screening tests mentioned by Mendoza were cytology, HPV 16 and 18 genotyping, p16/ki67 dual staining, and OncoE6.

“Another public health problem in the Americas is infection by emerging and re-emerging arboviruses with endemic and epidemic potential,” she said. “There are still countries in the region with little data on ecological and epidemiological aspects of arboviral infection. As a result, it’s vital to undertake collaborative research that can contribute data to strengthen monitoring and control of these viruses.”

Molecular research center

The use of modern molecular tools in medical research and diagnosis was the focus of a presentation to FAPESP Week by João Bosco Pesquero, a professor at the Biophysics Department of the Federal University of São Paulo (UNIFESP).

“Constant research efforts in the physiology of the human body and the interaction between genotype and phenotype are needed if we are to create new possibilities for health intervention,” he said. “One of the main goals of human genetics is to understand how changes in DNA drive the development of diseases. The greatest challenge of all is finding correlations between genotype and phenotype.” Pesquero is a member of FAPESP’s Health Sciences Area Panel.

Next-generation sequencing has led to major advances in medicine, Pesquero added. “Molecular biology and genetic studies of disease are vital to progress in screening and molecular diagnosis, and to the development of new therapeutic approaches and prevention. It’s important to promote wellness and combat sickness,” he said.

“To do this, we’re setting up a center for molecular research and diagnosis that will be a very important omics tool to help address the clinical challenges we face: a new benchmark for genetic and molecular research in Brazil.”

The center is being installed at UNIFESP with FAPESP’s support.

“We’ve sequenced diseases for countries throughout Latin America,” Pesquero said. “We’re entering the era of personalized, or least stratified, genomics. We must learn to read the genetic instructions for human beings more effectively.”

Read more about FAPESP Week Montevideo: www.fapesp.br/week2016/montevideo.