Fernando Garcia de Mello

Fernando Garcia de Mello

Fellow: Awarded 1984
Field of Study: Neuroscience

Competition: Latin America & Caribbean

Universidade Federal do Rio de Janeiro

Fernando Garcia de Mello obtained a degree in biochemistry from the State University of Rio de Janeiro in 1968 and a medical degree from the Medical School of the Federal University of Rio de Janeiro (UFRJ) in 1972.  While still an undergraduate student, he began his scientific training in the Scientific Initiation Program, which Dr. Carlos Chagas Filho instituted and which would become an official program at research universities throughout Brazil. This program led many students to appreciate the beauty and logic of science at an early stage of their formal university education and was the impetus for many of them to pursue a career in science. As part of this program, Dr. de Mello started working at the National Cancer Institute under Dr. Hugo de Castro Faria, focusing on the metabolism of amino acids and enzymes involved iwth the process of gluconeogenesis in rat livers.  During this period of intense laboratory work, Dr. de Mello was also working toward his biochemistry degree and later his medical degree.  In 1969, he joined the Biophysics Institute, one of the most important scientific institutions in the country, founded by the extraordinary Dr. Filho.  There, sponsored by Dr. Firmino Torres de Castro, he worked with the metabolism of proteins and nucleic acids of the protozoan Tetrahymena pyriformis. Working with Drs. Filho and de Castro was a great privilege and a defining experience for him, strongly influencing his humanistic attitude toward the people he encountered.  In 1973, the Biophysics Institute awarded him an M.Sc. degree.

At the end of 1973, Dr. de Mello took up a Fogarty Foundation postdoctoral fellowship at the National Institutes of Health (NIH/USA), working under Dr. Marshall W. Nirenberg. This proved to be a defining experience in his life, shaping his future work as a neurochemist and nurturing his growth as a professional scientist.  In that exciting scientific environment, he was greatly influenced not only by Dr. Nirenberg, but also by fellow postdoctoral students: Donald Puro, Hiroshi Matsuzawa, Hiroyuki Sugiyama, Matt Daniels, Uriel Bachrach, William Catterall, William Klein, and Zvi Vogel, among others, contituted important professional and human resources that would allow him to develop outstanding work in the years to come, and resulted in collaborations that yielded important publications.

At NIH, after many months of working with neuroblastoma cell lines, the predominant study model at Dr. Nirenberg’s lab, Dr. de Mello became involved in Zvi Vogel’s and Matt Daniels’ investigation of avian retinal tissue. Using this tissue, he started researching the developmental profile of the synthesis of GABA in the retina.  He observed that GAD (glutamic acid decarboxylase), the enzyme responsible for GABA synthesis, was very low in the early stages of development of the chick retina and that, as the tissue matured, GAD activity increased several times over. He also observed that despite the low GAD activity of undifferentiated retinas the level of the transmitter GABA was very high, suggesting an alternative source of the neurotransmitter in the retina of young embryos.  Indeed, Dr. de Mello demonstrated taht the alternative source of GABA in the embryonic retina was putrescine, a compound that is present in high levels in the undifferentiated nervous system with a high index of cellular proliferation.  This work constituted a set point for several publications by Dr. de Mello and other investigators that showed that GABA could influence developmental characteristics of the retina and of other areas of the nervous system.  Following these studies, several publications with Drs. Patricia Gardino and Jan Nora Hokoç revealed the main mechanisms used by retina cells to release GABA.  They also mapped the cell types that, upon activation of excitatory amino acid receptors, would release GABA and Signal GABAergic information in specific sites of the retina.

In 1975 M. Mackman  reported in Advanced Cyclic Nuceotide Research  (5: 661-679) that rat retina responded to dopamine with significant activation of adenilil ciclase. Dr. de Mello was already interested in the possible influences neurotransmitters might have on embryonic development of the nervous system. Using retinas at different stages of differentiation Dr. de Mello was able to show that exogenous dopamine was a highly efficient stimulator of adenylyl ciclase of the embryonic retina, at stages when dopamine was not yet synthesized in the tissue. This finding was one of the first demonstrations of the existence of functional neurotransmitter receptors in the developing nervous system prior to the existence of the endogenous neurotransmitter. Later on, as a Guggenheim Fellow at Northwestern University and then back in Brazil, in several publications Dr. de Mello and his collaborators confirmed that dopamine could indeed influence several neurobiological and neurochemical aspects of the developing retina. Among the most important findings in this area was the observation that dopamine could influence the motility and extension of growth cones of cultured retina neurons. In a recent publication with Dr. Jan Nora Hokoç he showed  that dopamine reduces the number and neuritic complexities of dopaminergic amacrine cells developing in situ, therefore confirming its role in naturally developing tissue. With Dr. Rafael Linden he demonstrated that  induced apoptosis in undifferentiated rat retinas was protected by dopamine, and  Dr. de Mello and his collaborators were the first to show the desensitization and down regulation of the dopaminergic receptor/cyclase system upon chronic stimulation of cultured retina cells with dopamine. It was also shown that under stimulation of the dopaminergic receptors,  long-term exposure of cultured retina neurons to specific pharmacological dopaminergic receptor antagonists would lead the receptor/cyclase system of the tissue to a hypersensitive state. Moreover, by manipulating the levels of light that reached the retina of post hatched chicken, they showed, for the first time, that reduction of environmental light, by decreasing dopaminergic communication in the retina, could induce a hypersensitive state of the retina dopaminergic system. To date, this seems to be the most direct demonstration of how environmental conditions can influence the level of response mediated by dopamine in specific dopaminergic circuitry of the nervous tissue. The list of important contributions of Dr. de Mello and his collaborators on dopaminergic research can be appreciated in several other publications. With former graduate students and collaborators, Dr. de Mello showed for the first time that dopamine, besides mediating cellular communication via classical dopaminergic receptors, also directly interfered with the excitatory amino acid receptor NMDA. They demonstrated that dopamine, at physiological concentrations, directly interacted with the NMDA channel (in the open-channel configuration) inhibiting  more than 50 percent of the time the conductance of the channel. This was first found in isolated retina neurons and later confirmed to be true in neurons of other areas of brain. Recently, other group of investigators has mapped the site, inside the NMDA channel, that binds dopamine (and apparently other catecholamines) and reduces the conductance of the NMDA receptor. At first, Dr. de Mello and others put those findings aside, because it might simply indicate that another charged compound could interact with the NMDA channel. However, due to pharmacological evidences that in some diseases affecting human behavior the dopaminergic system might be involved, Dr. de Mello`s and his collaborators original findings are now attracting attention. For instance, in schizophrenia  at least two pharmacological hypotheses explain what is known in the field as “positive and negative symptoms” of the disease. It is suggested that the positive symptoms are related to overactivity of dopaminergic circuitries in brain areas that use classical dopaminergic communication, mediated by dopamine receptors. The negative symptoms of the pathology, on the other hand, have been attributed to low activity of NMDA mediated synaptic function in specific areas of the brain. Although simplistic, these hypotheses serve as a basis from which to approach biological studies of such a complex and devastating disease. The finding that dopamine may act on both systems activating the classical dopamine receptors and inhibiting the NMDA channel, makes it highly relevant to studies of the neurobiological basis of psychological disorders.

One of Dr.de Mello`s major concerns, for many years, has been the fact that in the embryonic retina the capacity of some neurons to respond to dopamine precedes, by several days, the capacity of dopaminergic amacrine cells to express the property of synthesizing dopamine, apparently the only source of this catecholamine in the mature tissue. Over the years he has consistently brought this problem to the attention of his collaborators. Recently, with a then graduate student Regina Kubrusly and other collaborators, Dr. de Mello has found that, prior to the expression of the enzyme tyrosine hydroxylase, limiting step in dopamine biosynthesis in the nervous system, the embryonic retina expresses L-dopa decarboxylase that can convert L-dopa into dopamine, provided L-dopa can reach the retinal tissue. In fact when this compound was exogenously applied to the embryonic retina, in stages when tyrosine hydroxylase is not yet expressed by the tissue, the retina is not only capable of synthesizing dopamine, but also to use the catecholamine for the proper activation of dopaminergic receptors already present in the tissue at the early stages of development. Dr. de Mello´s group has also shown that the alternative source of L-dopa to the embryonic retina is the retina pigmented epithelium, upon which the retinal tissue is attached and formed during development. Therefore, an interplay between the retina pigmented epithelium and the neuroretina seems to be crucial to allow dopaminergic communication to take place in the developing neuroretina, before the tissue displays the capacity of synthesizing its own catecholamine. The pigmented epithelium expresses tyrosinase that, like tyrosine hydroxylase in neurons, forms L-dopa in the epithelium. L-dopa can diffuse out into the adjacent neuroretina where it is converted into dopamine via L-dopa decarboxylase. These findings may have tremendous implications not only for the concept of dopaminergic systems, but also for the understanding of the neurological disorders observed in albino animals and in humans. Albinism, in some cases, is associated with defects in tyrosinase, which incapacitates the epithelium to synthesize L-dopa. Therefore, in this condition, the influence that dopamine derived from L-dopa from the pigmented epithelium might have on the developing retina would be lacking and could be one of the causes of retinal defects in albinos.

Using the retina as a model to study neurochemical interactions in the nervous system, Dr. de Mello made important contributions to the study of the neurochemistry of the cholinergic system. In several collaborations with Drs. Nibaldo Inestrosa and Sergio T. Ferreira they used cultured retina neurons to show that the amiloidogenic (a-beta) peptide mediated its neurotoxic effects via increased availability of extra cellular glutamate. Moreover, with Venezuelan Ph.D. student Nelson E. Loureiro-dos-Santos, Dr. de Mello has shown that overexposure of cholinergic neurons to glutamate or glutamatergic agonists results in an irreversible inactivation of the choline acetiltransferase (ChAT) enzyme responsible for the synthesis of acetylcholine in the nervous system. Most interesting is the fact that the inactivation of ChAT seems to be due to post-translational modifications of the enzyme and not due to neuronal loss or degradation of enzyme molecules. This finding seems to have implications for Alzheimer`s disease, since the first neurochemical changes in brains of Alzheimer`s patients seems to be a deficit of cholinergic communication in areas associated with memory storage.

Dr. de Mello’s intense collaborations with different groups of scientists in Brazil and Latin America have produced important contributions to different areas of biology. Most important are those in biochemistry of protozooans, a field that Dr. de Mello has consistently been interested in since first studying T. pyriformis as a scientist in training. His publications with Drs. George A. dos Reis, Marcela Lopes, Wanderley de Sousa, and Mécia M. de Oliveira on Trypanosoma cruzi and Toxoplasma gondii interactions with host cells have had important implications in the field of parasite biochemistry and biology. Recently Dr. de Mello developed with Dr. Jan Nora Hokoç an in vitro retina model to study T. gondii infection of the nervous system.

As a result of his intense scientific activity Dr. de Mello has graduated over fourteen Ph.D. students, all now leading important research groups throughout Brazil and South America. In addition to his researches, Dr. de Mello has always taught classes on biochemistry, physiology, and neurobiology to undergraduate students of different schools and departments, including medical students. Every year, his laboratory offers a practical course on neurochemistry, at the graduate level, that has become a tradition in the Biophysics Institute and elsewhere. A large number of young neuroscientists now working in different universities of the country have taken this course as a set part of their curricula. The laboratory run by Dr. de Mello is still highly active, with his personnel ranging from undergraduate to postdoctoral students.

Besides teaching  graduate and undergraduate courses at the Federal University of Rio de Janeiro, Dr. de Mello was invited, on different occasions, to teach graduate courses in the Clemente Estable Institute in Montevideo, Uruguay. In two occasions (early and mid 1990) he was invited to teach a neurochemistry course at the department of Zoology of the University of Coimbra, Portugal. Later this department created a graduate program in neurosciences at that University that, under the leadership of his friend Dr. Arselio Pato de Carvalho, became one of the leading neurochemistry groups in Europe. Dr. de Mello has always mentioned his pride in participating and contributing to that successful initiative by Dr. Pato de Carvalho in Portugal.

Recently Dr. de Mello was one of the coordinators of the IBRO School that took place in Rio de Janeiro. Students from all over Latin America had the opportunity to share with their Brazilian hosts the most modern approaches to the study of neurochemistry. Dr. de Mello`s lab has always been open to students from many parts of the Country and abroad. He had the opportunity to welcome in his lab students and professionals from different universities of Brazil and from Chile, Uruguay, Venezuela, and Spain, all seeking to benefit from his expertise. On several occasions those contacts resulted in long-term collaborations and friendships.

During his career, Dr. de Mello has been honored by several renowned international institutions. In 1980 he received the Gustavo Lessa Award from the Brazilian-American Institute of Rio de Janeiro to develop research projects in the USA.  In 1989 he was appointed member of the Brazilian Academy of Sciences. In 1991 and 1995 he was nominated for membership in the Third World Academy of Sciences (TWAS) and the Latin American Academy of Sciences, respectively. In 1998 the President of Brazil conferred on Dr. De Mello  the Order of Scientific Merit, in the “Comendador” category. In 2003 he was invited to join the World Innovation Foundation (FWIF) as a Fellow of that organization.

Dr. de Mello has been an invited lecturer and also chairman of round tables and symposiums at many national and international conferences. He was the Chairman of the ISN-Satellite Meeting on “Cell communication in the nervous system: function and dysfunction” that took place in Rio de Janeiro in 2001. He is author or co-author of more than 120 papers presented and published in the form of abstracts in different scientific meetings. Dr. de Mello has published more than eighty full papers in the most respected scientific journals worldwide.

Dr. de Mello has also devoted significant time to administering scientific institutions and programs. He was chairman of the Department of Molecular Biophysics in 1991-1992 and of the Program of Neurobiology in 1999 –2001. He was twice,vice-director and director of The Biophysics Institute Carlos Chagas Filho between 1992 and 1998. Also, he was elected member of the council of the International Society of Neurochemistry (ISN), serving from 2002 to 2005.

Various Brazilian institutions have generously and consistently supported Dr. de Mello’s projects. He is a top-level Research Fellow of the National Research Council (CNPq), the main governmental institution financing research in Brazil. For the last nine years Dr. de Mello has been the coordinator of a multilaboratory research project on neurochemistry and neurobiology, sponsored by Federal and State Institutions of Brazil.



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