The search for new therapeutic targets for what are known as lymphoproliferative disorders, a group of disorders that includes neoplasias such as leukemia, lymphoma and myeloma, has been the focus of the Molecular and Cellular Biology Laboratory in the Hematology and Hemotherapy Division, Department of Clinical and Experimental Oncology at the Federal University of São Paulo (Unifesp).

The group’s coordinator, Professor Gisele Wally Braga Colleoni, presented advances in identification of biomarkers associated with multiple myeloma, in Columbus, Ohio on the final day of FAPESP Week Michigan-Ohio. The symposium was held March 28 – April 1 for the purpose of promoting increased cooperation between scientists from São Paulo and the United States.

“Multiple myeloma is still an incurable disease. Despite advances in the use of immunomodulatory drugs, proteasome inhibitors [important pathways for degradation of proteins inside cells] and autologous bone marrow transplants, the disease, at some point, ends up recurring. The five-year survival rate after diagnosis is currently only 35%. So there is still a lot of progress that needs to be made before we understanding its mechanisms and how to treat it,” said Colleoni in an interview with Agência FAPESP.

As explained by the researcher, the disease is characterized by the uncontrolled proliferation of a type of immune system cell known as a plasma cell, derived from B-lymphocytes and responsible for producing antibodies (proteins like immunoglobulin, responsible for humoral immunity). These cases account for 1% of all cancers and 10% of the hematologic neoplasias.

“When the malignant proliferation of plasma cells occurs in a localized manner, usually in the bones or facial sinuses, it is called plasmacytoma. When it occurs in systemic form, it is classified as multiple myeloma,” Colleoni explained.

In more advanced cases, the level of bone marrow plasma cell infiltrates increases considerably and begins to occupy the space of the other blood products, compromising system functioning. The most common symptoms are bone pain, infections, anemia and kidney failure.

The Unifesp group began its search for biomarkers of multiple myeloma 15 years ago when it became a member of the task force of the Clinical Cancer Genome Project, led by Marco Antonio Zago, then professor and currently president of the University of São Paulo (USP). The study is currently funded by FAPESP through the thematic project entitled, “Identification of biomarkers and possible therapeutic targets in B-cell lymphoproliferative disorders”.

“From 2000 to 2008, we received funding from FAPESP to collect and store samples of bone marrow and serum from all multiple myeloma patients in treatment at the Hospital São Paulo at Unifesp. Ever since, we have continued to collect and analyze this material and compare it with normal cells for the purpose of identifying genes and important pathways for cellular functions that are differentially expressed in tumors,” Colleoni said.

The group observed that in 90% of the samples of multiple myeloma, there was increased expression of the TRIAP1 gene, an inhibitor of apoptosis (programmed cell death) that quite possibly helps tumor cells survive and thus represents a potential therapeutic target. In tests conducted in vitro, silencing the TRIAP1 gene induced the death of a large percentage of the tumor cells.

“We have still not been able to conduct in vivo tests because there is no pharmacological inhibitor for the TRIAP1 gene, and when we silence the gene in cell culture, the cells die before we are able to obtain a sufficient number to implant in animal models in order to induce tumor formation,” Colleoni explained.

The group then decided to utilize a murine model to test pharmacological inhibition of the HSP70 gene, which provides support to the TRIAP1 gene and in this way, also helps tumor cells survive. According to Colleoni, the HSP70 gene is usually hyperexpressed in several types of cancer, including myeloma. The therapy was tested together with a proteasome inhibitor known as bortezomib.

“We achieved good results with the HSP70 gene inhibitor in vitro, but in the animal model, we have not yet been able to reduce the size of the tumor in an efficient manner, unrelated to the isolated or associated use of bortezomib. We are currently adjusting the model,” Colleoni said.

Other research fronts

The Unifesp group has also worked on other fronts in searching for therapeutic targets to fight multiple myeloma. One of them involves development of a vaccine designed to stimulate the immune system to recognize and attack tumor cells. According to Colleoni, since it is a disorder that originates in the defense cells, the B cell-mediated immunity (humoral) is often quite compromised.

The group identified proteins that are expressed in a considerable number of the tumor cells, including MAGEC1/CT7 and MAGEA3/6, with high immunogenic potential, in other words, with the capacity to induce immune cell response (mediated by T-lymphocytes). The findings caught the attention of other research groups, among them one led by Kris Thielemans at the Free University of Brussels in Belgium, and another led by Professor Sara Saad at the University of Campinas (Unicamp).

“In this case, we proposed the collection of immature cells from the patient’s own immune system to be treated and sensitized in vitro with the tumor antigens. Once they have matured, these cells will be reused in the patient with the hope that they will attack the tumor cells. Before that however, other treatments have to be used to reduce the tumor burden,” Colleoni said.

Thielemans’ team has used a similar method in experimental treatments of melanoma. Colleoni stresses that this type of vaccine is specific to each patient however.

“It is not a commercial product. Immunotherapy however has been considered the greatest revolution in cancer treatment in the past five years and many significant results have been presented with the inhibition of proteins such as PD-1, PDL1 and CTLA4. This stimulates the T-lymphocytes to recognize the tumor and eliminate it,” the researcher said.

The search for therapeutic targets has also been focused what are known as bone marrow stromal cells. As Colleoni explained, this type of cell is found in every tissue of the body and serves as a support mechanism, producing growth factors, for example.

“Somehow, the tumor is able to reprogram these bone marrow stromal cells so that they begin to work to provide feedback to it. We are looking for a way to interrupt this communication and block the action of these stromal cells in order to help fight the tumor cell,” the researcher said.

Lastly, the team has been dedicated to investigating the existence of tumor stem cells in samples of multiple myeloma. Such cells could constitute an additional possible therapeutic target since they are able to promote the tumor’s recurrence or relapse through conventional treatment.

“We conducted the analysis using a technique known as flow cytometry. We started from the data in the literature, indicating that these cells, if in fact they exist, should be expected to express some markers of pluripotency such as the proteins ALDH+ and CD34+. The studies also indicate that since they are considered myeloma stem cells, they cannot express protein CD138,” she explained.

Some of the data presented by Colleoni was published in articles in the journals: Biochimica et Biophysica Acta (BBA) – Molecular Basis of Disease; Cancer Immunology, Immunotherapy; Cancer Letters; and Cancer Immunity.

Osteoarthritis

In the same session dedicated to the topic of “Medicine and Health,” Professor Sudha Agarwal of the Biosciences Division at the Ohio State University, presented data from a FAPESP-funded project carried out in partnership with Mario Ferreti Filho, a professor from the Department of Orthopedics and Traumatology at Unifesp.

The goal of the study was to understand the mechanism through which performance of moderate physical exercise improved inflammation in the cartilage of carriers of osteoarthritis. Through experiments with bioluminescent mice, the group showed that training modulates the expression of several genes and alters the balance of inflammatory and anti-inflammatory molecules in the body, improving inflammation in a systemic manner.

The researchers are currently trying to identify biomarkers that are able to indicate to what extent the patient is responding to the therapeutic interventions.

Also taking part in the Friday afternoon panel was researcher David Symer, associated with the Ohio State University Comprehensive Cancer Center, and University of São Paulo Medical School (FMUSP) Professors Marta Imamura and Linamara Battistella.

Karina Toledo, in Ohio | Agência FAPESP

Sponges are animals (of the phylum Porifera) that do not have nervous, digestive or circulatory systems. Because they do not move, they rely on maintaining a constant water flow through their bodies to obtain food and oxygen. They are very simple organisms, but they stand out due to certain characteristics.

One characteristic is that they are pioneers. Sponges are the first animals to inhabit the earth, according to several studies, including that carried out by researchers at the Massachusetts Institute of Technology and published in the March issue of the journal Proceedings of the National Academy of Sciences.

Through the use of genetic analyses, the group has confirmed the existence of sponges 640 million years ago, nearly 100 million years before the Cambrian explosion when most major animals appeared on the planet.

Another characteristic that makes sponges attractive as a subject of research is the fact that they hold significant medicinal potential. This is due to the presence of chemical compounds in them that may be used to produce medicines to fight viruses, bacteria and even tumors.

The discovery and development of natural products with bioactive potential using marine organisms is one of the main lines of research of the group headed up by Professor Roberto Gomes de Souza Berlinck at the São Carlos Chemistry Institute (IQSC) of the University of São Paulo (USP).

“There are many marine organisms that are the source of a wide variety of small molecules we call secondary metabolites, because they are not essential for the survival of these organisms,” he said.

“Although secondary metabolites are not very important for these animals, they are critical for the survival of several species, in which, for example, they play a role in chemical defense or in protecting against bacteria,” said the researcher who leads the thematic project entitled, “Biodiversity components of Brazilian islands and their metabolic role – an integrated approach”, funded by FAPESP.

Berlinck’s group discovered metabolites in sponges that were found to produce compounds active against leishmania and trypanosomes, the parasites that cause Leishmaniasis and Chagas disease, respectively.

“It is important to find new drugs to fight these diseases because those that are currently available to treat Leishmaniasis, for example, have been used for a long time and are very toxic,” he said.

“We carried out a detailed study of the various antiparasitic compounds we discovered, such as alkaloids, and have conducted in vivo and in vitro analyses on the mechanisms through which these compounds present pharmacological activities,” Berlinck went on to say.

Metabolites found by the researchers in sponges of the species Monanchora arbuscula, collected off the southeastern coast of Brazil, have led to the isolation of a series of guanidine and pyrimidine alkaloids with antiparasitic action against Trypanosoma cruzi and Leishmania infantum.

“And it is important to point out that these compounds affect these specific parasites and not humans, which is an advantage in treating the diseases they cause,” Berlinck said.

The findings of the study carried out by the IQSC-USP group together with scientists from the Adolfo Lutz Institute of the University of British Columbia (Canada) and other institutions, was published in 2015 in the Journal of Natural Products.

New materials

Berlinck was one of the speakers at FAPESP Week Michigan-Ohio, held March 28 – April 1 in the United States. On the event’s final day, in Columbus, Berlinck took part in a panel discussion entitled “Materials and Manufacturing,” along with Chris Hammel and Carlos Castro of the Ohio State University, Marcelo Knobel (Brazilian Nanotechnology National Laboratory (LLNano) and Unicamp) and Holmer Savastano Junior (USP).

At the laboratory he heads up in the Department of Physics at OSU, Hammel and his group are developing systems to produce nanometric scale images and trying to understand dynamic interactions in magnetic structures.

For example, the researchers are studying the behavior of spin-based electronics (which explores the quantum propensity of electrons to spin) on different materials and the phenomena that occur in magnetic and microscopic structures and various types of complex materials.

Knobel talked about the research studies he is coordinating, especially with regard to the magnetic properties of nanocrystals. In a study published in Scientific Reports, by the Nature group, Knobel and his colleagues at Unicamp and the National Synchrotron Light Laboratory (LNLS) described a new method that has potential applications in the field of health.

The researchers discovered how to pause the process of thermal decomposition of iron with the presence of silver particles, resulting in the formation of a type of nanoparticle with interesting properties.

According to Knobel, implementation of the method is relatively simple and could contribute to the development of nanoparticles that can be used to transport medicines.

Castro, born in El Salvador, presented the studies he is conducting to develop DNA-based nanometric devices in the Department of Mechanical and Aerospace Engineering at OSU.

The goal is to produce systems that are capable of self-assembly according to the DNA structure, and that can be programmed and controlled for various applications, such as transporting medicines.

Savastano, a professor in the Faculty of Animal Science and Food Engineering, and head of the Research Center on Materials for Biosystems at USP talked about using sustainable materials in manufacturing.

The researcher coordinates the FAPESP-funded thematic project entitled Agrowaste, which is investigating the potential use of agroindustrial waste in materials for housing and infrastructure (roads, for example).

In his talk, Savastano pointed out the study conducted using the curauá (Ananas erectifolius), whose fibers demonstrate mechanical properties that are superior to other plants and that may be an important alternative as reinforcement in cement-based compounds in the construction industry.

The study was carried out together with Victor Li in the Department of Materials Science and Engineering at the University of Michigan, funded by that U.S. university and FAPESP.

Heitor Shimizu, in Columbus (EUA) | Agência FAPESP

Corruption, a topic that stubbornly remains in the forefront, has many aspects as well as many costs. In a system in which favoritism of one means disadvantage for another, someone always pays the price for illegal or improper benefits. And that price is even higher in poorer countries.

According to economist Pranab Kumar Bardhan, professor emeritus at the University of California, Berkeley, the cost of corruption is particularly high in developing economies since it introduces inefficiency into a system that is already at a disadvantage. If the economy is not doing well, the inefficiency promoted by corruption makes things worse.

Amanda Lea Robinson, a professor in the Department of Political Science at Ohio State University, is studying the main targets of corruption in precisely those developing countries. She is not studying who is suffering the most or paying the most, but instead who most often faces what is called “petty corruption” in their day-to-day lives.

“It is abuse of power by low and mid-level public officials in their interactions with ordinary citizens,” she explained.

Robinson analyzed one country in which corruption is “endemic at all levels of government” and where 79% of the population considers corruption to be one of the main factors that limits development: the eastern African country of Malawi.

Her study, conducted in collaboration with Brigitte Seim, a professor at the University of North Carolina in Chapel Hill, mainly involved cases with highway patrol officers. A previous study had indicated that 95% of the population considers police in that country to be corrupt.

“The officers weigh the potential benefits of asking for kickbacks – such as the citizen’s ability and desire to pay, the certainty of payment and the amount of the kickback – against the potential costs: the capacity and desire of the citizen to punish the officer through formal or informal means,” she said.

According to Robinson, when stopping a vehicle that has committed some infraction on the highway, that has overdue tags or stickers, or has done something that could lead to imposition of a fine, the patrol officer assesses the type of vehicle and the characteristics of the driver to determine whether or not he will take a chance and ask for a kickback if he agrees not to enforce the penalty.

The study involved six workers in Malawi, who drove around the country’s roads using different automobiles, outfits and accessories that indicated whether they were wealthy or poor. They also used some type of indicator of political party or ethnic affiliation while sometimes driving expensive vehicles and other times driving inexpensive vehicles.

“During the survey conducted in June 2014, 52% of the time that the workers drove along the selected highways, they were stopped by the police. In only 3% of the cases was a fine imposed, but in 90% of the cases, the police asked for kickbacks,” Robinson said.

One might assume that the poorest would face more corruption in their daily lives, and thus be subjected to being asked to pay kickbacks, but this was not what happened.

The study found that political connections reduced the chance of paying kickbacks in 11% of the cases while socioeconomic status had no effect. According to Robinson, this suggests that corruption is more frequently associated with politics than with the financial circumstances of the individuals involved.

In the examples with low socioeconomic level and no political connections, 91% of the sample resulted in the payment of kickbacks. When the driver indicated high socioeconomic status, but an absence of political connections, the results were the same.

High socioeconomic status and absence of political connections led to the payment of kickbacks in 86% of the cases. The fewest number of cases of kickbacks occurred when the driver indicated that he had political connections, but low socioeconomic status.

“We think that this is due to the contradictory impact of wealth on corruption in societies with substantial inequality. Wealthier individuals can increase the benefits of corruption by paying higher kickbacks, but in so doing, they also increase their costs if they are able to corrupt officers,” Robinson said. In other words, the next time, because they have more money, they will pay more.

If on the one hand the fieldwork done in Malawi indicated the protective effect of political connections, the researchers found evidence that ethnicity had an opposite effect, increasing the exposure to corruption, especially in contexts where it was most endemic.

“We think this effect is motivated by the elevated levels of trust between people of the same ethnicity. This interpersonal trust makes the officers feel more inclined to ask for kickbacks,” said the Ohio State professor.

Robinson points out that if this is really the case, “it is another context in which elevated social capital can have negative effects. She says that “the perverse effect of social capital” is something she plans to study further.

Robinson went on to say that the study “is informing the scientific literature, programs and policies that attempt to document and deal with discrimination against the poorest and least favored in society,” and she stresses that the results found in Malawi should not be generalized for use in other contexts.

“In any event, our findings suggest that the costs of corruption fall more heavily on some segments of the population than on others. Such discriminatory practices incur great losses on the social fabric of any society, even more so for those who struggle with underdevelopment, inequality and ethnic divisions,” she said.

Heitor Shimizu, in Columbus (USA) | Agência FAPESP

Bioinformatic tools have been used by researchers at the Federal University of the ABC (UFABC) and the University of São Paulo (USP) to model genetic interaction networks, reveal functional relationships and thus identify targets for the treatment of complex diseases such as schizophrenia, autism and cancer.

Advances in this field were presented by David Corrêa Martins Junior, a professor from the Center for Mathematics, Computation and Cognition (CMCC) of the UFABC on March 31 in Columbus, Ohio during FAPESP Week Michigan-Ohio. The event that ends Friday (4/1) was designed to promote increased collaboration among researchers from the U.S. and São Paulo.

Some of the findings have also been published in articles in the journals Information Sciences and BMC Bioinformatics.

“A single complex disease can manifest itself in many different ways in each individual, with varying degrees of severity. The goal of this type of study is to be able to offer individualized treatment, taking into account these particularities,” Martins Junior explained in an interview with Agência FAPESP.

The studies are based both on clinical data – gene expression, interaction among proteins and DNA methylation – held in public databases as well as data from patients under the care of collaborators such as Professor Helena Brentani of the Psychiatry Institute at the University of São Paulo (IPq-USP) who works with carriers of autism.

Concepts from graph theory and complex networks, together with bioinformatics tools, are enabling scientists to compare gene expression and centrality in the gene networks between carriers of a particular disease and individuals in a control group. It is also possible to compare data from patients with the same disease but different degrees of severity, or even to evaluate how gene expression and the structure of a gene network in one person changes in different contexts and at different times. The idea is to try to discover how the genes are connected and how this circuit controls the various cell functions.

“When we don’t know the function of a gene, we can try to compare its expression or the structure of its vicinity in the gene network with others that present a similar signal and whose function is known, and thus formulate a hypothesis. If we have a target gene and we want to know to what extent its expression depends on the signal from other genes, we can use tools like gene network inference or gene prioritization,” Martins Junior explained.

According to the UFABC researcher, genes that have already been associated with diseases in previous studies can serve as a starting point for analyses. “We can evaluate which of the other genes are most closely associated with them in terms of expression and in terms of connective structure. Most likely, they will also be involved in the disease in question,” he said.

In a post-doctoral research study conducted by Sergio Nery Simões during his graduate program in bioinformatics at USP, a tool known as NERI (Network Medicine Relative Importance) was developed that integrates gene expression data, protein integration networks and data from association studies (genes known to be associated with a particular disease) to identify new genes that may also be associated with the illness in question.

“We did a case study using public databases on schizophrenia and saw that many of the genes obtained by the NERI tool were associated with the so-called glutamatergic pathway, responsible for the transmission and reception of neurotransmitters during neuronal synapse. This pathway is well-cited in the literature as being associated with the disease. This suggests that other genes identified by the tool also have the potential of being related to schizophrenia,” Martins Junior explained.

The group’s research is funded by FAPESP through two thematic projects – one coordinated by João Eduardo Ferreira at the Institute of Mathematics and Statistics (IME) at USP and the other by Roberto Marcondes Cesar Junior  also at the IME-USP. There is also a regular research grant coordinated by Raphael Yokoingawa de Camargo at the CMCC-UFABC.

Analysis of social networks

On the same panel dedicated to “Bioinformatics and Data Analytics,” OSU Computer Science and Engineering Professor Srinivasan Parthasarathy talked about how information collected on social networks such as Twitter or WhatsApp can be used to predict or mitigate problems related to natural disasters and epidemics.

Working in partnership with researchers from several countries, including Brazilians associated with the Federal University of Minas Gerais (UFMG), Parthasarathy is gathering and analyzing information from short messages sent during extreme climatic events such as hurricanes and floods or during epidemic outbreaks and using the contents to feed computer models. The goal is to identify problems before they become critical and provide information that can help teams that render assistance to the site to plan control strategies.

“If I have 5,000 people available to provide assistance, I have to identify the areas most affected that need to be prioritized. To that end, we use the information collected from social media together with the physical data that traditionally feeds the hurricane and flood prevention models, such as wind and atmospheric pressure, which come from a more traditional form of sensing,” the researcher explained.

The greatest challenge, according to Parthasarathy, is the ability to filter messages that are actually related to the problem in question. “There is a lot of noise on social networks. For example, if our objective is monitoring a dengue epidemic in a particular city, we have to be able to isolate the tweets that originated in that area and include that information in our model. By integrating social and physical sensors, we can produce better results,” said the researcher.

Also taking part in the panel convened during FAPESP Week were Álvaro Montenegro, a professor in the Department of Geography at Ohio State University, and João Luiz Filgueiras de Azevedo of the Aeronautics and Space Institute (IAE).

Karina Toledo, in Ohio | Agência FAPESP

After two days of presentations and discussions at the University of Michigan, FAPESP Week continued Thursday (3/31) on the campus of the Ohio State University, nearly 300 km to the south.

One of the largest public universities in the United States, the Ohio State University (OSU) was founded in 1870 and is home to 15 schools occupying 570 buildings. It offers more than 450 undergraduate and graduate courses and welcomes nearly 58,000 students. OSU invests nearly $1 billion in research annually.

In 2013, FAPESP and Ohio State signed a cooperation agreement under whose scope there have been two calls for proposals issued and 43 projects selected, bringing Ohio researchers together with those from the state of São Paulo.

Carlos Henrique de Brito Cruz, FAPESP scientific director, explains that historically, the Foundation has mainly supported Brazilian researchers who travel to the U.S. university and researchers from Ohio State who travel to São Paulo State institutions. “But since 2013, we have greatly expanded our collaboration by issuing calls for proposals,” he said.

“The results of this joint work can be seen in the large number of articles written in recent years by researchers from the state of São Paulo with their colleagues from Ohio State. This number jumped from 40 a year in 2009 to nearly 300 in 2015,” he said.

“The number of article citations has also increased significantly, up from an average of 35, already considered high, demonstrating that these are articles that have achieved visibility in their respective fields,” he said.

Caroline Whitacre, Vice President for Research at Ohio State University, noted that the projects selected in the joint calls for proposals with FAPESP involve work in the most diverse fields of knowledge.

One example Whitacre put forth was a project about Chagas disease, directed by Sergio Schenkman of the Federal University of São Paulo (Unifesp) and Bradford S. McGwire of Ohio State, selected in the first round of calls for proposals.

The project enhanced collaboration between laboratories led by the two scientists in studies of the mechanisms through which the protozoan parasite Trypanosoma cruzi survives and becomes capable of causing infection after passing through the intestines of the triatomine bug.

From the second call for proposals, whose results were announced in December 2015, Whitacre mentioned projects such as, “Metagenomics and proteomic analysis of individuals with generalized aggressive periodontitis and their descendants,” led by Purnima Kumar of Ohio State and Renato Correa Viana Casarin of the University of Campinas (Unicamp).

“According to our agreement, Ohio State and FAPESP spend approximately $1.4 million in funding collaborative projects selected through calls for proposals,” Whitacre said. The agreement is for five years, “but we definitely want to continue our partnership with FAPESP,” she said.

Brito Cruz went on to say that the close relationship with Ohio State extends to the FAPESP Executive Board, whose administrative director, Joaquim José de Camargo Engler, received his PhD in agricultural economics from Ohio State and was presented with the entity’s International Alumni Award in 1994.

Growing collaborations

Brito Cruz gave the opening address at the event, where he talked about science and technology in São Paulo and FAPESP’s role in developing research in the state.

The scientific director said that the state of São Paulo – where 1.7% of the GDP is allocated to research and development, a sum much higher than anywhere else in Brazil – accounts for close to 45% of all science produced in Brazil, according to the number of scientific articles published in international journals.

He went on to talk about some of the research programs sponsored by FAPESP, such as those involving scholarships and grants, and about the Foundation’s system for evaluating requests for funding.

Brito Cruz then talked about the importance to the Foundation of cooperation agreements with universities, companies and organizations in Brazil as well as in dozens of other countries.

“We have a program that involves research centers that bring together universities and industry, for example. One of these centers is the Protein Kinase Chemical Biology Center housed at the University of Campinas (SGC-Unicamp). It is a partnership between the University of Oxford, the University of Toronto and Unicamp,” he said.

“Researchers at the SGC-Unicamp work with colleagues from the other two universities as well as colleagues from several large pharmaceutical companies for the purpose of discovering kinases [groups of enzymes] and processes related to kinases that the industry can then use to study proteins or develop new drugs,” he said.

“And we are happy to welcome Aché as the first Brazilian pharmaceutical company to become part of the SGC-Unicamp. We just finalized the terms of the contract governing how it will participate, and now there is a Brazilian company involved in this tremendous effort in science, research and technology,” he said.

Supported by the FAPESP Research Partnership for Technological Innovation Program (PITE), the center is part of the Structural Genomics Consortium, which brings together researchers from universities, pharmaceutical companies and other organizations.

“Another growing type of collaboration is that in which FAPESP and its university partners offer seed funding to researchers so they can prepare proposals that can be presented to funding agencies in their home countries and in Brazil,” Brito Cruz said.

Whitacre then spoke about the Discovery Themes Initiative, a long-term program at Ohio State that brings university students and professors together with representatives from other institutions.

According to Whitacre, the program is designed to “find lasting solutions to critical societal needs” and is divided into thematic research areas such as Materials and Manufacturing for Sustainability, Infectious Disease, Foods for Health, The Humanities and the Arts, Sustainable and Resilient Economy and Data Analytics.

“The Discovery Themes program is a model of interdisciplinarity and transinstitutionality that promotes and enhances broad university collaboration and represents an excellent opportunity to approach major global issues,” Whitacre said.

Heitor Shimizu, in Columbus (USA) | Agência FAPESP 

Although slavery was officially abolished in Brazil in 1888, it is still possible nowadays to find workers subjected to conditions analogous to slavery.

According to an assessment recently released by the Ministry of Labor and Social Security (MTPS), in 2015 alone, the problem has been detected in 90 of the 257 establishments inspected, and a total of 1,010 people were removed from labor conditions considered degrading.

In an attempt to understand the factors that characterize the phenomenon of contemporary slavery, Rebecca Scott, historian and professor at the University of Michigan Law School, has dedicated herself to the study of documents produced by MTPS employees during inspections.

The project has been carried out together with Federal Justice Carlos Henrique Borlido Haddad ,who is also a professor at the Federal University of Minas Gerais (UFMG), and Leonardo Augusto de Andrade Barbosa, a legal analyst in the Brazilian Chamber of Deputies in Brasília.

Scott presented the scope of the study March 29 in Ann Arbor, Michigan during FAPESP Week Michigan-Ohio. The event, which ends April 1 in the city of Columbus, Ohio, is designed to promote cooperation between scientists from São Paulo and the United States.

“The campaign to eradicate labor analogous to slavery that has been carried out in Brazil since the mid-1990s – and which has gained renewed intensity mainly in the early 21st century – involves several government and non-government entities and has generated what historians most long for: a vast amount of documentary material. I know of no other country that has undertaken such a systematic study in this field,” Scott said in an interview with Agência FAPESP.

Analysis of the cases generated by MTPS inspection, said Scott, is allowing researchers to go beyond speculation and confirm actual conditions that are leading prosecutors and judges to convict individuals for exploitation of slave labor.

“It is allowing us to examine legal concepts, understand how the inspectors and promoters diagnose the situation when they visit the work sites, and observe how these legal concepts are evolving in society,” she said.

The collaboration with Brazilian legal experts began nearly two years ago, when they were in Michigan engaged in post-doctoral studies. Haddad had practical experience in the subject since he had served as judge in several cases where employers were accused of exploitation of slave labor. In 2009, at the Federal Court of Marabá, in the Brazilian state of Pará, he presided over 32 cases, convicting 27 individuals in a single block of decisions.

“Haddad believes that society as a whole is undermined when this type of situation goes unpunished. Barbosa was very interested in studying how the laws were written and how they have changed,” Scott went on to say.

Scott said she was particularly interested as an historian in defining the concept of contemporary slavery. “The use of this term is intended to make it analogous with circumstances found in 19th century Brazil. But how can we use this metaphor without making a mistake? We cannot diminish the unique characteristics of the process of 19th century African slavery. Determining the line between slavery and freedom is critical for the forward progress of the campaign to eradicate the problem,” Scott explained.

According to the researcher, the analyses have indicated that “conditions analogous to slavery” are those in which violations of labor laws exceed a certain limit and begin to assail human dignity.

“Employers often sense vulnerability in their employees and act to capitalize on this, thus diminishing the degree of autonomy an individual has in accepting certain working conditions. Another part of this are the working conditions themselves. For decades, studies have shown that slavery tends to place humans in conditions similar to those of animals, such as by making them sleep outside, for example,” she explained.

New sources

In addition to the MTPS documents, the group soon plans to examine the collection found in the offices of the Labor Public Prosecutor (MPT) at the 15th Region of Campinas, which is in the process of being digitized with funding from FAPESP under the scope of the thematic project “Between slavery and the burden of freedom: workers and forms of labor exploitation in historical perspective.” The project is headed up by University of Campinas (Unicamp) Professor Fernando Teixeira da Silva, who is a member of the team from the Social History of Culture Research Center (Cecult).

As described by Sidney Chalhoub – who is now a professor at Harvard University, but was once a faculty member at Unicamp and is still a member of the Cecult team –, the MPT collection was in danger of being destroyed due to lack of storage space, and it was saved thanks to FAPESP funding, which has allowed it to be digitized. The database currently includes a total of 3,228 files, 1,053 of which are already available for public consultation at Unicamp.

“A considerable portion of the material from the Labor Court had already been destroyed due to lack of storage space which is a pity. We’re talking about an incredibly rich source of material that historians can use to study the experiences of laborers from a particular time period. Much of what we know today with regard to slavery was found in the testimony provided by illiterate workers in criminal and civil cases,” Chalhoub said.

In addition to Scott and Chalhoub, the session devoted to topics in law and social justice included University of Michigan history professors Paulina Alberto, Jean Hébrard and Sueann Caulfield, besides Brazilian Eduarda La Rocque who coordinates the initiative known as Rio’s Pact – which is a participatory public-private partnership involving public, private and academic sectors, non-for-profit organizations, the general public and international bodies. Its aim is to promote and monitor sustainable development of the Rio de Janeiro metropolitan area.

Karina Toledo, in Michigan | Agência FAPESP

In 2015, 3.5 billion passengers traveled by air, this according to the International Air Transport Association (IATA). The number is expected to double by 2034 when Brazil, one of the countries in which the industry has grown most rapidly, is expected to have more than 200 million passengers per year.

“The aviation industry has an enormous impact on the global economy and there is nothing better for rapid travel over long distances than aircraft, which offer a method that is reliable and safe,” said Carlos Cesnik, director of the Active Aeroelasticity and Structures Research Laboratory at the University of Michigan (UM) and professor of Aerospace Engineering.

But, just as it will grow, the industry will go through may changes in the coming years, says Cesnick and the other speakers on a panel that presented alternative technologies for the future of aviation at FAPESP Week Michigan-Ohio, which runs through April 1 in the U.S.

The group led by Professor Daniel Inman of the Aerospace Engineering Department at UM has pursued alternatives for developing more efficient aircraft starting with the study of those who fly most in the world: birds.

According to Inman, the idea for modifying the wings of aircrafts is very old. The Wright brothers themselves used wings that could change shape as they were pulled by cables. “They wanted to learn how to fly and what better way to do that than by using birds as an example,” he said.

However, for reasons of safety – reducing turbulence, for example –, rigid surfaces have dominated aviation from when the industry first became popular up to the present. And it has only been in recent years that interest has again turned to the study of wing configurations that change shape during flight.

“In our study, we do not want to copy how birds flap their wings, but instead, analyze features in the physiology of these creatures that can inspire technological solutions, particularly in applications using intelligent materials,” Inman said.

His group, which includes engineers and experts in animal biology – from UM, Stanford and the University of California Los Angeles –, just this month received a $6 million research grant from the U.S. Air Force Office of Scientific Research to produce the most detailed analysis of bird flight ever conducted in an aeronautical engineering project. “We will be studying the most varied types of birds, in terms of size, shape and speed,” he said.

While today’s aircraft have rigid wings and use parts known as flaps, slats and spoilers for control, birds use their feathers – either singly or combined – to create surfaces that control flight. And there is one other important detail: they do this without wasting energy. That is the main objective of Inman’s research: harness the efficiency of bird flight for use in the aviation industry.

New shapes, new materials

In Brazil, the group led by Edson Cocchieri Botelho, a professor at the School of Engineering of the State University of São Paulo (Unesp) in Guaratinguetá, has studied the use of heat resistant plastic materials in the aviation sector.

Known as composite materials because they have at least two components or two phases, these materials have distinct physical and chemical properties. They are polymeric materials that stand out due to a favorable combination of low specific mass and high mechanical performance.

“Most of the advanced polymeric composites currently in use are obtained from reinforced thermosetting resins that nevertheless present stress problems due to processing and the brittle nature of the resin,” Botelho said.

“Thermoplastic polymers reinforced with continuous fibers are becoming an important replacement when compared with conventional thermosetting polymers because they present higher values of rigidity and impact resistance, higher service temperature and greater versatility in series production,” he said.

In a study funded by FAPESP, Botelho and his team processed thermoplastic composites with different degrees of crystallinity and evaluated the influence of this crystallinity on mechanical and thermal performance involving a variety of environmental conditions.

The project was carried out together with the Aerospace Technical Center (CTA), the Composites Institute of Kaiserslautern and the Leibniz Institute of Polymer Research in Dresden, both of the latter in Germany.

“We have studied structural as well as carbon nanotube reinforced composite materials in joint research studies with groups from the U.S. universities of California, Purdue, Case-Western and Washington,” Botelho told Agência FAPESP.

Much of Brazil’s efforts to develop new technologies aimed at the aviation sector takes place in São José dos Campos as might be expected.

An example was presented during FAPESP Week by João Luiz Filgueiras de Azevedo, coordinator of a research group at the Aeronautics and Space Institute (IAE) of the Department of Aerospace Science and Technology (DCTA), which works primarily with computational fluid dynamics.

The researchers run computer simulations to analyze factors such as velocity, turbulence, pressure, temperature and others that have considerable effect on aircrafts.

The key areas of research are in developing computer and modeling systems and studying factors such as turbulence, aeroacoustics, elasticity, fluid structure interaction, hypersonic flows and aerodynamic optimization.

Heitor Shimizu, in Michigan | Agência FAPESP

In an effort to kick start implementation of precision medicine in Brazil, members of five of the 17 FAPESP-funded Research, Innovation and Dissemination Centers (RIDC) met in mid-2015 to establish the Brazilian Initiative on Precision Medicine (BIPMed).

The initial findings of this partnership were presented March 28 during FAPESP Week Michigan-Ohio by one of the project founders, Iscia Lopes-Cendes, a professor at the School of Medical Sciences of the University of Campinas (FCM-Unicamp).

Included in the initiative are the Center for Computational Engineering and Sciences (CCES), the Center for Cell-Based Therapy (CTC), the Obesity and Comorbidities Research Center (OCRC) and the Center for Research on Inflammatory Diseases (CRID), lead by the Brazilian Research Institute for Neuroscience and Neurotechnology (BRAINN).

“The first product launched under the scope of the BIPMed was a public genetic database, the first of its kind in Latin America, that can be accessed at http://bipmed.iqm.unicamp.br/,” said Lopes-Cendes.

According to her, the database has already received information from 29 people from the region of Campinas in upstate São Paulo who underwent sequencing of the whole exome, the part of the genome that holds the protein-encoding genes, where disease causing mutations are most likely to occur.

By analyzing data from the 29 exomes currently in the database, the group has found 209 genetic variants that have not been described in any other database in the world, but it is still not known whether or not these genomic variations are related to diseases.

“We already have exome sequencing data from 250 other people ready to be included and analyzed. It is important to stress that we are not talking about patients, but rather about a reference population of people who are healthy, as far as we know. We recruit these volunteers from among those who accompany the patients receiving medical care at the Hospital de Clínicas at Unicamp and it is therefore constitutes a representative sampling of the genetic structure of the patient cohort in the BRAINN studies,” Lopes-Cendes explained.

Also included in the database was information about the presence of more than a million molecular markers of single-nucleotide polymorphisms (SNPs) in 200 individuals of the reference population.

“These SNPs are genetic variations that can be found in any part of the genome, not just in the protein-encoding part. The difference is that instead of sequencing the whole genome, we use a microarray technique with specific probes. SNPs are common molecular markers, found in at least 5% of the population that may or may not be related to the development of diseases,” Lopes-Cendes explained.

As explained by the researcher, these genomic variations that occur outside the protein-encoding region do not usually cause disease, but serve to provide an idea of the genetic structure of the population.

An example of the clinical importance of this knowledge was presented by Lopes-Cendes during FAPESP Week Michigan-Ohio as well as published in the article in the journal Acta Neurologica Scandinavica.

In the study, the team from BRAINN analyzed data from 76 patients receiving medical care at the Hospital de Clínicas at Unicamp who carried a neurological disorder known as dystonia. The disease is characterized by involuntary contractions in one or more muscles that can be painful and intense. Unlike Parkinson’s disease, dystonia can affect people of any age.

“We initially studied the clinical characteristics of our patients and confirmed that they constituted a representative sampling from around the world, in other words, they presented the same conditions as dystonia patients from other countries. We then investigated the two genetic mutations most commonly associated with the disease on the TOR1A and THAP1 genes,” the researcher said.

According to Lopes-Cendes, there is an international recommendation to investigate the presence of these two mutations in all carriers of dystonia symptoms in order to establish the diagnosis and identify other family members who may carry the disease.

“However, the study results showed that the TOR1A mutation was not even found in our sampling, while an alteration in the THAP1 gene was found at a much lower frequency than that described in the literature. This indicates that international recommendations are not necessarily valid for Brazil, which has a population whose genetic structure is much more heterogeneous as a result of crossbreeding. That is why it is important to have a genetic database that is representative of our population,” said Lopes-Cendes.

According to her, the group’s studies show that other genetic variants described in international studies as the cause of serious disease were often found in the reference population included in the BIPMed database.

“To make sure that a mutation does in fact cause disease, it cannot be found in healthy individuals. But this analysis is only possible if we have data from a representative population of that individual. If we only look at international databases, we could get false results,” she added.

Karina Toledo, in Michigan | Agência FAPESP

Global climate change is imposing risks on cities and leading to the need for them to develop adaptation plans. But how can cities like São Paulo, that have so many other infrastructure and development problems develop an adaptive capacity that allows it to efficiently respond to the challenges imposed by climate change?

Finding answers to this question is one of the objectives of a study conducted by scientists at the University of São Paulo (USP) and the University of Michigan (UM), with funding from FAPESP and the U.S. university.

According to the project coordinators, professors Gabriela Marques Di Giulio at the School of Public Health at USP, and Maria Carmen Lemos, at the School of Natural Resources and Environment at UM, the growing realization that mitigation alone will not be enough to avoid the impact of climate has led to an increase in the number of cities all over the world that are presenting adaptation plans that recognize the risks associated with climate change and the impacts it will have on their socioeconomic systems.

Despite this, there are many other cities at risk that have done little. And their reasons for this include economic, institutional or political constraints that reduce the capacity to provide basic services, infrastructure and support to their populations.

Di Giulio and Lemos, who presented their findings on March 28 at FAPESP Week Michigan-Ohio, which runs through April 1 in the U.S. cities of Ann Arbor and Columbus, point to the fact that studies have identified resources and governance structures that are increasing the likelihood of successful adaptation. And understanding how these resources interact both positively and negatively is essential in building more resilient and sustainable cities.

“São Paulo, for example, which is our focus of research, is part of the C40 Cities Climate Leadership Group [network of megacities committed to facing the challenges involved in global climate change] and is one of the few megacities that has a municipal policy on global climate change, instituted in 2009, although most of the objectives have yet to be achieved,” Di Giulio said.

According to her, in São Paulo the challenge is integrating public policies related to climate change with policies that pertain to housing, sanitation, urban planning, water resources management and urban mobility.

“It’s a highly heterogeneous metropolitan region in terms of access to resources, poverty levels and the ability to act together in dealing with climate change,” she said.

“From our research, we have tried to understand how a megacity, in the case of São Paulo, has mobilized itself to address the risks and threats posed by climate change, how the decision makers in science, policies and civil society perceive climate risk at the local level, and how contextual factors are influencing local adaptive capacity,” she said.

Di Giulio explained that the research is based on qualitative methods that include review of the scientific literature, documentary research – analysis of public opinion surveys, journalistic content, documents and socioeconomic data –, interviews with actors and social groups, and technical and scientific meetings.

The joint project funded by FAPESP and the University of Michigan includes two researchers in the state of São Paulo and one in Michigan, in addition to Di Giulio and Lemos.

The researchers have already conducted four project tasks since October 2014 that included holding a seminar, a workshop and meetings in São Paulo and in Michigan.

Among the project findings, Di Giulio mentioned the publication of articles such as Building adaptive capacity in the megacity of São Paulo, Brazil: urgencies, possibilities and challenges, presented in 2015 at the RC21 International Conference, sponsored by the International Sociological Association, in Italy and “Megacities and climate change: an interdisciplinary focus on the city of São Paulo,” to be published in 2016 as a chapter in a book.

Other Brazilian cities

“We’re building an analytical platform to better understand the complex process of adaptation, especially when we consider the uncertainties related to projections regarding climate and the frequency of extreme events. In terms of contextual factors that are directly influencing adaptive capacity, we are also examining how economic, institutional and political constraints affect the ability of cities to provide basic services and support their current populations, infrastructure and ecosystems,” Di Giulio said.

According to the study, the population in São Paulo tends to view climate change as a minor problem. “People recognize the impacts of climate change, but although they are worried, for them the impacts compete with other matters that are more pressing,” Di Giulio said.

The researchers are analyzing recent urban policies in São Paulo, among which are specific interventions in systems of mobility, housing and sustainable infrastructure initiatives, but they believe that these and other measures have not been described as actions for adapting to climate change.

The project continues with development of the CiAdapta (Cities, Vulnerability and Climate Change), an integrated and interdisciplinary approach for analyzing actions and adaptive capacity. The new project, which goes through 2017, is funded by the National Council for Scientific and Technological Development (CNPq). CiAdapta involves six Brazilian state capitals: São Paulo, Manaus, Fortaleza, Vitória, Curitiba and Porto Alegre.

Another project carried out by Lemos and Di Giulio involves cities in the state of São Paulo. “We plan to develop a theoretical and methodological platform to analyze climate adaptation that applies to all the cities whose populations range between 20,000 and 500,000 inhabitants. We initially developed a questionnaire that has been distributed to these cities with the collaboration of the São Paulo State Department for the Environment,” said Lemos, who did her undergraduate work at the Federal University of Juiz de Fora and earned her master’s and PhD at the Massachusetts Institute of Technology.

“It’s important to emphasize that what the cities have done up to now to prepare themselves for global climate change along with the platform we are developing can help not only in making decisions in the study cities, but in other Brazilian cities as well,” said the UM professor.

Heitor Shimizu, in Michigan | Agência FAPESP

Several studies aimed at finding genes related to the development or progression of diseases such as cancer and hypertension were presented March 28 in Ann Arbor, Michigan during FAPESP Week Michigan-Ohio.

The event, which runs through April 1 in the cities of Ann Arbor and Columbus, was organized by FAPESP together with the University of Michigan (UM) and the Ohio State University (OSU) for the purpose of promoting increased cooperation between scientists from São Paulo and the United States.

Among the speakers was endocrinologist Antônio Marcondes Lerario, of the University of Michigan Medical School, whose work is directed at identifying targets for the treatment of adrenal cortical carcinoma (ACC), a rare type of cancer characterized by abnormal growth of the outer layer (cortex) of the adrenal glands, which are located on top of the kidneys.

The adrenal cortex plays an important role in the endocrine system because it produces hormones that regulate metabolism and blood pressure. It also synthesizes cortisol and the male hormones known as androgens. ACC manages to unleash an overproduction of these hormones.

“From the clinical standpoint, the disease is quite heterogeneous. There are cases linked to inherited mutations, but most are sporadic. Some patients do well while others do not. We are identifying biomarkers that help distinguish these different cases,” Lerario said.

Besides surgery to remove the tumor, treatment of the disease includes chemotherapy, radiation and medications that block the production of cortisol when the levels of this hormone are very high.

According to Lerario, there are, however, no efficient options for treating advanced cases of the disease in which metastasis has occurred. “What we can do is begin aggressive chemotherapy, which improves symptoms a little, but does not affect overall survival. That’s why our research is geared towards the identification of specific molecular targets that can be blocked through the use of drugs and thus reduce disease progression without affecting healthy tissue. It’s what we call targeted therapy,” he explained.

Several candidate genes are being investigated at the University of Michigan Medical School. One of these therapeutic targets – IGF-2 (Insulin-like growth factor 2) – has been used in clinical trials, but did not demonstrate the expected effectiveness.

“IGF-2 is a gene that is hyper expressed in 90% of the carriers of adrenal cortical carcinoma and we know that it causes proliferation and growth of cells. We tried to use drugs that blocked the receptor of this particular protein. It worked in vitro and in animal models, but in humans, only 5% of patients responded,” the researcher said.

The 5% that responded presented significant improvement, however. The disease stopped progressing for a prolonged period of time, and in some cases even began to regress. According to Lerario, it is still impossible to know in advance which patients will respond to this therapy.

“It is a complex disease. In addition to the IGF-2, there are other active oncogenic pathways and what appears to be a synergy between them. Our goal now is to find ways to simultaneously engage several of the pathways or determine whether there is a central pathway,” Lerario said.

Resistant hypertension

The relationship between treatment-resistant hypertension and excess activation of cell receptors for the aldosterone hormone (known as a mineralocorticoid receptor) was the topic of the lecture presented by Professor Bryan Byrd of the Cardiovascular Medicine Division of the University of Michigan Medical School.

According to Byrd, patients considered to be treatment-resistant are those whose blood pressure remains above goal despite concurrent use of ideal doses of three medications of different classes, one of which should be a diuretic.

“The best statistics we have on these cases are Brazilian, provided by researchers at the Heart Institute (InCor) of the University of São Paulo School of Medicine (FMUSP), and they indicate that the problem affects approximately 10% of hypertensive patients,” Byrd said.

Among these cases of actual resistance to therapy, the researcher went on, 20% of the patients present excess activation of the system related to the aldosterone hormone, which causes the kidneys to retain larger quantities of water and sodium.

“During the process of evolution, the mineralocorticoid receptor emerged when mammals left the aquatic environment. Its mission was to prevent death due to dehydration. The activation of this receptor tells the kidney that it should retain water and sodium in situations in which finding water is difficult. But some people seem to produce high levels of the aldosterone hormone even when they drink sufficient amounts of water and ingest a lot of salt in their diets,” Byrd explains.

The researcher added that recent studies have shown that even some hypertensive patients with normal levels of aldosterone in the blood respond well to drugs that block the activation of the mineralocorticoid receptor.

“This suggests to us that there may be other ways to activate this receptor, perhaps through molecules with action similar to aldosterone that still need to be identified. Another possible explanation is that these patients have a superexpression of the mineralocorticoid receptor. Our studies are trying to identify the precise cause of this exaggerated activation of the system,” Byrd stated.

In the same session, Gisele Colleoni, a researcher at the Federal University of São Paulo (Unifesp), presented a line of research focused on finding therapeutic targets and predictive biomarkers for multiple myeloma, a type of cancer that affects cells of the immune system known as lymphocytes.

Nils Walter, a chemistry professor at the University of Michigan, talked about the use of fluorescence microscopy as a non-invasive tool for examining, in live cells, the role of RNA molecules that do not encode protein, but play a role in regulating gene expression and may be involved in the development of diseases.

USP researcher Alexandre da Costa Pereira presented initiatives aimed at mapping the genetic structure of the Brazilian population (highly heterogeneous as a result of the crossing between various ethnicities) and discussed how knowledge of genetic variants can help identify susceptibility in developing chronic diseases.

Karina Toledo, in Michigan | Agência FAPESP