{"id":168230,"date":"2014-12-29T16:01:15","date_gmt":"2014-12-29T18:01:15","guid":{"rendered":"http:\/\/revistapesquisa.fapesp.br\/?p=168230"},"modified":"2015-03-25T15:20:11","modified_gmt":"2015-03-25T18:20:11","slug":"a-deep-rooted-lineage","status":"publish","type":"post","link":"https:\/\/revistapesquisa.fapesp.br\/en\/a-deep-rooted-lineage\/","title":{"rendered":"A deep-rooted lineage"},"content":{"rendered":"
\"Neuronal

Riccardo Cassiani-Ingoni \/ Science Photo Library<\/span>Neuronal embryonic stem cells forming neural networks, seen through fluorescence microscopyRiccardo Cassiani-Ingoni \/ Science Photo Library<\/span><\/p><\/div>\n

\u201cThey\u2019re here!\u201d shouted a student of geneticist Mayana Zatz upon bursting into the classroom at the Human Genome Research Center (HGRC), in an annex to the Biosciences Institute of the University of S\u00e3o Paulo (IB-USP). The student was referring to the newborn pups of two female golden retrievers, both carriers of muscular dystrophy, a neuromuscular disease that leads to progressive weakening of the muscles and an inability to move. The dogs are part of a stem cell study, an important component of HGRC research efforts, along with more traditional studies such as those associated with the human genome. \u201cWe injected the stem cells into dogs with dystrophy for the purpose of trying to reverse the effects of the disease,\u201d Zatz explains.\u00a0 In a previous study on the same breed, her group observed that some of the animals carried genes that neutralized the negative effects of the mutation responsible for the dystrophy.\u00a0 The dogs had a genetic alteration associated with the disease, which prevented them from producing dystrophin, an essential protein for maintaining muscle integrity.\u00a0 None of the dogs presented the classic signs of dystrophy, such as difficulty in walking, however.<\/p>\n

Zatz believes neuromuscular diseases are perhaps the first to benefit from stem cell studies. In cases of muscular dystrophy, she explains, there is muscle degeneration and, despite the fact that the body has many muscles, it is easier to replace an area of affected tissue than it is to make a new muscle through the use of stem cells.\u00a0 In 2012, Zatz\u2019 group concluded that injecting adult human stem cells together with administering daily doses of a growth factor could be a possible alternative to the treatment of progressive muscular dystrophies in mice.\u00a0 In the study published in the journal Stem Cell Reviews and Reports<\/em>, the group reports that while the combination did not generate new muscles, it reduced the inflammation and fibrosis in the existing muscle.<\/p>\n

Zatz\u2019 successful research studies in the field of stem cells and in other areas of genetics have made her one of the most visible Brazilian scientists in the world.\u00a0 As professor at the Biosciences Institute, the geneticist has headed up the HGRC, one of the FAPESP-funded Research Innovation and Dissemination Centers (RIDC), since 2000.\u00a0 In all, the group led by Zatz has already cared for 20,000 people suffering from neuromuscular diseases. \u201cIt is the largest sample in the world studied at a single center,\u201d she says. \u201cToday, we\u2019re following the second generation of these patients.\u201d\u00a0 The research and patient care conducted at the HGRC is one of the legacies left by geneticist Oswaldo Frota-Pessoa, who died in 2010 at the age of 93. One of Brazil\u2019s pioneers in human and medical genetics, he was Zatz\u2019 undergraduate advisor in the 1960s.\u00a0 At the time, he was already caring for people with a variety of genetic diseases. \u201cIn his view, the patients helped generate new research studies, so the new studies had to help the patients,\u201d Zatz explains. \u201cFrota-Pessoa trained all the medical geneticists of my generation as well as the generation that preceded me.\u201d<\/p>\n

Born in Rio de Janeiro in 1917, Frota-Pessoa studied natural history at the University of the Federal District. In 1941, he graduated from what was then known as the University of Brazil.\u00a0 Still in Rio de Janeiro at the time, he began to collaborate with geneticists from USP, led by Andr\u00e9 Dreyfus, one of those responsible for bringing Russian biologist and naturalized American Theodosius Dobzhansky to Brazil from Columbia University where he had introduced the genetic study of drosophilae (fruit flies). Dobzhansky is remembered as a researcher that made numerous requests for study trips, resources and equipment.\u00a0 As a condition for coming to Brazil, he demanded a research trip to the Amazon region.\u00a0 Dobzhansky\u2019s visit influenced Frota-Pessoa to return to studying the Brazilian species of fruit flies during his doctoral program.\u00a0 In the 1960s, Frota-Pessoa was invited by Crodowaldo Pavan, another important member of the group that helped institutionalize genetics in Brazil, to set up a human and medical genetics unit in the Department of Biology at the Biosciences Institute. \u201cThis unit later became the HGRC,\u201d Zatz says.<\/p>\n

History of excellence<\/strong>
\nThe network of individuals who later enabled the establishment of groups of excellence at USP in human genetics and genomics began to take shape in the 1930s, a decade marked by establishment of activities at USP in 1934.\u00a0 The history of these individuals is often mixed with the history of that university \u2014 the IB-USP building, which houses the Department of Genetics and Evolutionary Biology, is named after Andr\u00e9 Dreyfus, for example. Its halls display signs of history at every turn.\u00a0\u00a0 Among them are scattered the pieces of the collection of the Institute\u2019s memory, including photographs, fossil collections, statues and even a cabinet belonging to Crodowaldo Pavan.<\/p>\n

\"Crodowaldo

IB-USP Memory Committee Collection <\/span>Crodowaldo Pavan helped start the center for human genetics and medicine at the Biosciences InstituteIB-USP Memory Committee Collection <\/span><\/p><\/div>\n

The Biosciences Institute was established in 1969. It included the departments of biology, botany, physiology and zoology, established in 1934 together with the Chair of General Biology, occupied by Andr\u00e9 Dreyfus at the USP School of Philosophy, Literature and Human Sciences (FFLCH). Dreyfus was among members of the committee tasked with developing the project to establish S\u00e3o Paulo\u2019s first public university. It was admiration for him that led Harry Miller Jr. of the Rockefeller Foundation to fund the purchase of laboratory equipment and research, and to bring Dobzhansky to Brazil to give a course on evolution, attended by nearly all biologists of USP, the Biological Institute of S\u00e3o Paulo and the Campinas Institute of Agronomy (see Pesquisa FAPESP<\/em> Issue No. 168).<\/p>\n

Today, the third floor of the IB building is the site of the Molecular Genetics Laboratory, created in 1996 through a FAPESP-funded project and since then led by geneticist Lygia da Veiga Pereira. A physics graduate of the Pontifical Catholic University of Rio de Janeiro (PUC-RJ), Pereira came to the Biosciences Institute motivated by the work of the groups led by Mayana Zatz and biologist Angela Morgante, whose master\u2019s and doctoral advisor was Frota-Pessoa. In 2008, Pereira\u2019s group announced that it had obtained the first Brazilian lineage of embryonic stem cells, BR-1, from a single embryo frozen three years earlier. To get to the BR-1 lineage, Pereira says, 250 embryos had to be defrosted, of which only 35 developed to the fifth day, the stage at which the cells are able to be extracted. \u201cThis is how we replace imported stem cells and develop our own technical competence to obtain and maintain these lineages,\u201d Pereira says.<\/p>\n

Up to now, her laboratory is the only one in Brazil to produce human embryonic stem cells.\u00a0 Pereira\u2019s group recently obtained funds for construction of the National Laboratory of Embryonic Stem Cell Research (LaNCE), which will produce lineages for clinical use.\u00a0 \u201cThe other part of the stem cells produced in the future laboratory will be used in testing for drug response,\u201d she says.\u00a0 Another important project developed in the laboratory involves what are known as induced pluripotent stem cells, mature cells that can be reprogrammed to again become able to generate a number of different body tissues.\u00a0 \u201cWe have developed a technique used to produce these cells here in the laboratory,\u201d Pereira says.\u00a0 \u201cUsing these, we plan to compile a library of pluripotent cells that represent Brazilian genetic diversity.\u00a0 In the future, we would like to be able to test the drug response of cells derived from the pluripotent cells in in vitro<\/em> experiments.\u201d<\/p>\n

Since 1996, Pereira\u2019s group has dedicated a portion of the laboratory resources to the study of Marfan syndrome, a genetic disorder characterized by the development of very long limbs, along with such things as cardiovascular, ocular and bone complications. Clinical manifestations of the syndrome in humans are quite varied, the geneticist explains.\u00a0 \u201cMembers of a single family with the same mutation can develop different problems. One person might have a cardiac problem, while another develops an ocular complication.\u201d\u00a0 In studies using genetically modified mice, the researchers are trying to identify the genes that interact with the gene responsible for the syndrome, which causes two people with the same disease to develop different complications.<\/p>\n

Recognition<\/strong>
\nThe golden days of the Biosciences Institute, according to biologist and professor in the USP Botany Department, Marie-Anne Van Sluys, perhaps came during the time of sequencing the genome of the Xylella fastidiosa<\/em> bacterium, responsible for citrus variegated chlorosis, also known as yellowing disease, which at the time affected 34% of the orange groves in the state of S\u00e3o Paulo. Van Sluys and her husband, molecular biologist Carlos Menck of the USP Biomedical Sciences Institute, were part of a group of 190 researchers from various institutions and fields that, through a virtual network of 60 laboratories, worked on what was considered to be the largest science undertaking ever carried out in Brazil, targeting the genetic sequencing of an organism.<\/p>\n

\"A

Eduardo Cesar<\/span>A biomedical researcher handles stem cells grown in a greenhouse at 37\u00baCEduardo Cesar<\/span><\/p><\/div>\n

Launched in 1997 through the FAPESP Genome Program, the work of sequencing the 2.7 million chromosomal bases of\u00a0 Xylella<\/em>, according to Menck, enabled USP researchers to enter a new field of knowledge: bioinformatics.\u00a0 \u201cAt the time, it wasn\u2019t clear whether the sequencing would constitute progress for us. There was a lot of criticism!\u201d the researcher recalls. \u201cBut we became adept in terms of sequencing and data analysis technologies, especially with regard to bioinformatics, which had no community up to that point in Brazil,\u201d he says. \u201cAll of this represented a huge advance for USP research groups,\u201d he concludes.\u00a0 The project received international recognition in 2000 with publication of a cover story in the journal Nature<\/em> about sequencing of the bacterium\u2019s genetic code (see Pesquisa FAPESP<\/em> Issue No. 55<\/a>). \u201cIt is important to mention the work of Andrew Simpson, the project\u2019s DNA coordinator, whose enthusiasm never faded, and who never cut corners, allowing us to move forward,\u201d Menck recalls.<\/p>\n

For the ICB researcher, despite the important legacies left by the project, such as Alellyx, the biotechnology company founded in 2002 by Votorantim Novos Neg\u00f3cios, the USP researchers did not continue to make contributions to the field of bioinformatics.\u00a0 \u201cI believe one of the reasons for this was the difficulty in developing the field of genome bioinformatics that is still in its infancy at USP.\u201d In any case, \u201cthe genome projects had a tremendous impact on USP, but we could have gone much further if we kept groups working on sequence analysis studies, especially from the evolutionary perspective,\u201d he says. \u201cDobzhansky would have loved this!\u201d<\/p>\n

Successful sequencing of the Xylella<\/em> genome broadened the scope of the FAPESP Genome Program, which was later engaged in other projects of significant social and economic interest.\u00a0 One of them was the Sugarcane Genome Project known as the FAPESP SUCEST Project, which was responsible for mapping 238,000 functional sugarcane gene fragments.\u00a0 \u201cThe SUCEST project paved the way for the use of molecular markers in crop improvement,\u201d says molecular biologist Glaucia Souza, professor at the USP Chemistry Institute and SUCEST participant.\u00a0 Nearly 240 researchers from 22 institutions worked from 1999 to 2002 to identify the expressed sequence tags (EST) of sugarcane.<\/p>\n

\u201cThe project enabled us to learn about sugarcane metabolism,\u201d says Souza, who today coordinates the FAPESP Program for Research on Bioenergy (BIOEN) and SUCEST-FUN, which focuses on the functional analysis of sugarcane genes and the identification of genes associated with agronomic traits of interest. The group\u2019s work is directed towards such topics as generating transgenic plants and investigating genes associated with sucrose content, biomass, drought tolerance, phosphate deficiency and climate change.<\/p>\n

The researchers still want to understand how these genes work.\u00a0 Souza explains that initially, the project focused only on the functional DNA sequencing of sugarcane, ignoring the genes that had no known function.\u00a0 \u201cNow we\u2019re trying to identify strands of DNA known as promoters,\u201d she says.\u00a0 Under an agreement with the Microsoft Research Institute for a research study on sugarcane genomics, her group is working on the annotation and analysis of the gene activity, which could allow the cultivation of varieties with higher or lower quantities of sugar in areas with little water.<\/p>\n","protected":false},"excerpt":{"rendered":"The institutionalization of human genetics shapes excellent teams","protected":false},"author":346,"featured_media":0,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"_acf_changed":false,"_exactmetrics_skip_tracking":false,"_exactmetrics_sitenote_active":false,"_exactmetrics_sitenote_note":"","_exactmetrics_sitenote_category":0,"footnotes":""},"categories":[159],"tags":[211,209,237,250],"coauthors":[662],"class_list":["post-168230","post","type-post","status-publish","format-standard","hentry","category-science","tag-biochemistry","tag-biology","tag-genetics","tag-neuroscience"],"acf":[],"_links":{"self":[{"href":"https:\/\/revistapesquisa.fapesp.br\/en\/wp-json\/wp\/v2\/posts\/168230","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/revistapesquisa.fapesp.br\/en\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/revistapesquisa.fapesp.br\/en\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/revistapesquisa.fapesp.br\/en\/wp-json\/wp\/v2\/users\/346"}],"replies":[{"embeddable":true,"href":"https:\/\/revistapesquisa.fapesp.br\/en\/wp-json\/wp\/v2\/comments?post=168230"}],"version-history":[{"count":0,"href":"https:\/\/revistapesquisa.fapesp.br\/en\/wp-json\/wp\/v2\/posts\/168230\/revisions"}],"wp:attachment":[{"href":"https:\/\/revistapesquisa.fapesp.br\/en\/wp-json\/wp\/v2\/media?parent=168230"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/revistapesquisa.fapesp.br\/en\/wp-json\/wp\/v2\/categories?post=168230"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/revistapesquisa.fapesp.br\/en\/wp-json\/wp\/v2\/tags?post=168230"},{"taxonomy":"author","embeddable":true,"href":"https:\/\/revistapesquisa.fapesp.br\/en\/wp-json\/wp\/v2\/coauthors?post=168230"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}