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NEUROSCIENCE Connection without frontiers Cutting edge experiments with the travel from Duke University to Natal, along with the will to help science transform needy communities

MARILUCE MOURA, FROM DURHAM AND NATAL

Published in February 2007

es, it is a dream. Or rather, a transposition to the real world. And nothing seems to be more in tune with the spirit of someone who has tried insistently, for two decades, to capture and to decode in the brain the almost invisible signals of the connections be- tween thought and movement, intention and action, desire and realization. The name of this dream that is beginning to materi- alize with bricks, cement and high-level professionals in the - Yian Northeast is the International Institute for of Natal (IINN). Its dreamer-in-chief is Miguel Nicolelis, 45 years old, a respected neurobiologist from Duke University, born in São Paulo, who in 1984 grad- uated as a physician from the University of São Paulo (USP), and is known above all, despite the important contributions he has made to basic neu- roscience, for his advanced experiments with neural microelectrodes implanted in monkeys that, amongst other results, may lead to the de- velopment of prostheses for human beings, such as artificial arms and legs, that is, robotic limbs with movements commanded directly by the brain.

RITA SINIGAGLIA-COIMBRA/UNIFESP RITA Which is to say, by thought. Or by will. To prevent injustice, however, let

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Action at a could be inaugurated during the 2nd distance: Nicolelis Symposium of the International Insti- trained night tute for of Natal, from monkeys to move February 23 to 25. a mechanical arm There are three buildings, let it be ex- using the power plained, because one is intended to be the of the brain project’s Mother and Child Health Cen- ter, another to be the research center it- self, and the third, a community educa- tion center. From that, you can already perceive that Nicolelis and his closest companions are thinking of cutting edge research linked to social action, and they make no secret of that. So much so, that in the waiting room of the IINN's pre- sent building, which also houses the Al- berto Santos Dumont Association for Supporting Research (AASDAP in the Portuguese acronym), a notice on the wall advises visitors that this Civil Soci- ety Organization of Public Interest (Os- cip in the Portuguese acronym), creat- ed on April 17, 2004 precisely to make the institute viable,“has as its objective the management of its own and third party funds for the implantation of social and

JIM WALLACE/DUKE UNIVERSITY JIM WALLACE/DUKE scientific research projects”.It goes on:“It is based on the concept that cutting edge science can, in developing countries like Brazil, act as a powerful agent for the so- Brazilian team us include right away in the category of cial and economic transformation of co-dreamers from the institute, two of communities located in needy regions of at Duke thinks Nicolelis´s colleagues: Sidarta Ribeiro the national territory”. and Cláudio Mello. The first of the institute’s buildings up cutting edge Imagined from a distance since that the visitor coming from the state research linked 2002, inside a laboratory that had ex- capital sees in Macaíba, on the campus’s panded vigorously to its current 1,200 access road, on the right, is the health cen- to social action square meters at Duke, in Durham, ter. Some 500 meters further on, practi- North Carolina, this institute began to cally at the entrance to the campus, the operate in the middle of last year. At this research center appears.And further on, moment, it occupies a rented building the future installations of the communi- of 1,500 square meters in a simple street ty education center appear. A profusion in the capital of Rio Grande do Norte, of noticeboards in front of the works ad- very close to the Viasul shantytown, vises the visitor of the political and fi- while the more ambitious and solid nancial support for the enterprise: the forms of its own premises are going up federal government is represented by the on the campus of the Jundiaí Agricul- Ministry of Health and the Ministry of tural School, which belongs to the Fed- Education, through the Council for Ad- eral University of Rio Grande do Norte vanced Professional Training (CAPES). (UFRN), in Macaíba, a small city some Duke and UFRN appear on the notice- 20 kilometers from Natal. Note that boards, as does the municipal govern- Macaíba has no more than some 60 ment of Macaíba.What does not appear thousand inhabitants, while Natal is are the individual donors, like Lily Safra, around the 800 thousand mark. Last the widow of banker Edmond Safra, who January, in the midst of the bustle of at the end of 2006 gave the project a sum the workmen in three different build- that, at her request, has not been revealed ings in the institute under construction ,but that, according to Nicolelis, is the on the campus, the expectations were largest private contribution ever intend- high that part of these installations ed for a research venture in Brazil.

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et us temporarily leave Macaíba to return to the beautiful campus of Duke, which occupies fifth place in the ranking of the most respected research universities in the United States. It was a rather cold late fall afternoon, on LNovember 17, 2006. In one of the build- ings in the biomedical area of the cam- pus, in its large, reasonably organized room, divided into two areas, Nicolelis looked happy with the presentation made a few hours ago by the doctoral student under his supervision, Nathan Fitzsimmons, to qualify for his thesis. “In our specialization, everybody has to date managed to read signals that come from the motor areas of the brain. Ex- cept that when you move a robotic arm, you have to get signals back to under- stand where it is touching. And what we have managed, what he found, was ba- sically the formula, an algorithm for sending back signals to the brain, in a sensorial feedback! It was a very good presentation”,he comments.

RITA SINIGAGLIA-COIMBRA/UNIFESP RITA Attention: it is very recent develop- ments in the research with cortical im- plants of electrodes in mice and mon- keys that he is commenting on. In this In Durham, the group case, the work was with owl monkeys, or night monkeys – two little female mon- wanted to test whether keys, to be precise, Thumper and Pocie, as Nicolelis tells with wit in his blog on monkeys could learn to Globo Online. They are one of the mod- decode – to read, shall els closest to man, and the results could be of utmost importance, in terms of ap- we say — the message plication, precisely for the dreamt-of fu- ture prostheses commanded by the sent to them in the brain. Furthermore, in terms of basic sci- ence, they could add further information form of electrical about how learning effectively produces microstimulation and microanatomic transformations in the brain.“In short, the same electrodes used associate it with a to record electrical signals from the mo- tor areas have allowed us to pass a digi- movement tal message directly into the somesthet- ic cortex, the superficial region of the brain that identifies stimuli applied to the surface of the body, to see whether the brain learns to understand what is coming”,the researcher explains. In oth- er words, Nicolelis and his group want- ed to test whether monkeys would learn to decode – to read, shall we say – mes- sages sent to them in the form of elec- trical microstimulation, and associate them with a movement.“We went from something very simple, with a fixed pat-

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tern,to another more complex, mobile, In the neuroscientific literature, ac- And why is Nicolelis sure about that? with a space-time dimension.” cording to Nicolelis, the commands re- “We saw, with different algorithms sent In a first experiment, the animals garding movement are normally at- off at the same time, that over the pe- should learn to associate arbitrarily the tributed to introspection, when to stop or riod of learning, the process of the ar- electrical stimulus in the cortex to a to move is determined inside the brain it- bitrary message would transform itself movement to the left or to the right that self, and, in a pattern that the researcher into a clear motor command. For the makes it possible for them to find food calls second degree, to the external envi- first time, we were successful, at the same kept in compartments on one side or on ronment. So it is something cultural, time that we were stimulating the the other. For example, if the electrical learnt. One example is the immediate im- somesthetic cortex, in reading the sig- stimulus appears, it ought to go to the left, pulse of all motorists to stop the car when nals produced in another area of the and, if not, to the right. They took 40 days the traffic light turns to yellow, announc- brain, the motor area, and in decoding to learn. In the following experiment, with ing that the red light will be next. “In with precision the animals' intentions, a more complex pattern, with time vari- Brazil, though, something very peculiar the movement that they were going to ations, surprisingly, they took only ten happens, which is accelerating the car make, before performing it”,he details. days.“Probably because they generalized to go through on the yellow light”,the re- This with a time difference of 100 to 200 the information, and that gave them more searcher jokes. Amongst primates, and milliseconds. facility for learning”,Nicolelis observes. perhaps other mammals, stopping or go- In this field, incidentally, Nicolelis’s Afterwards, when the researchers revert- ing may also be determined by a verbal team has, at this point, begun even more ed the pattern learnt, each monkey learnt command “From that, I called it ‘a close exciting experiments with owl monkeys, the new pattern even more quickly: first, encounter of the third kind’ a message something that now appears to belong in four days, the simplest pattern, and in comes from an artificial system, a digital frankly to the realms of science fiction three, the most complex. The experi- command directly in the brain, which is and that he calls a “close encounter of ments continue, and, last November, the arbitrary and comes to have a meaning”, the fourth kind”.There are some im- researchers were starting to use 16 elec- he says. This abstract message connected pressive results, but he prefers to remain trodes in the experiment, instead of the with a motor command “produces a mi- cautious and not to reveal anything be- four used up until then. croanatomic transformation”,he adds. fore more certain confirmations. GIOVANNI SÉRGIO GIOVANNI

26 ■ SPECIAL ISSUE NOV 2006/SEP 2007 ■ PESQUISA FAPESP 22-31_Neuroscience_132_Ing 12/11/07 19:30 Page 27 GIOVANNI SÉRGIO GIOVANNI Concrete dream: workmen erect research (above) and community education centers n the IINN in Rio Grande do Norte, persons distributed between the insti- at this moment there are 12 re- tute’s main building and a second build- searchers working under the com- ing aimed at community health of the lo- mand of 35-year old Sidarta, the in- cal population, nearby. stitute’s scientific coordinator, as Sidarta graduated from the Univer- well as a floating population of vis- sity of Brasilia (UnB) in 1993, took a iting researchers. On the afternoon master’s degree in biophysics at the Fed- Iof January 11 last, for example, there was eral University of Rio de Janeiro (UFRJ) to be found amongst them Eduardo and a doctorate in cognitive molecular Schenberg, a pupil of Koichi Sameshima, neurobiology from Rockefeller Univer- a neurologist from the Syrian-Lebanese sity (1995-2000), and was finally brought Hospital, in São Paulo, an institution with into Nicolelis’s laboratory at Duke in which the IINN maintains a collabora- 2000, first as a postdoctoral student and tion agreement that is now showing in- next as an associate researcher, and he teresting results, particularly in studies of looks quite naturally upon his work as Parkinson’s disease. The installations in IINN coordinator. the institute’s rented premises, despite the On this point, let it be said that one intention to move a good part of the lab- of the criticisms of the IINN enterprise oratories to the new premises in Macaí- from part of the Brazilian neuroscientif- ba in the short term, are well prepared for ic community is precisely the way he con- an important part of the research with ducts the coordination, which some see electrodes – the rodents’ vivarium and as a sign of the closing up of Nicolelis’s the surgical center, for example, seem to group, instead of the expected opening be first class. And the building also has out and interaction with various other adequate rooms for experiments on hu- neurology groups in the country.“Sidar- man beings that are part of Sidarta’s line ta is a brilliant researcher, extremely of research on sleep and memory. Also promising, but the choice of him as sci- taking into consideration employees entific director was frustrating, because from the administrative area, there are 20 it does not appear to have been the result

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This dream began of a selection process with clear bases. self as the pioneer and founder of neu- The institute is now beginning to select roscience in Brazil. So each one of us in Juqueri in the researchers, postdoctoral students, but it wondered whether what we had done in all sounded very restricted at the outset, the last 30 or 40 years was not worth any- 1920s or 1930s. and that was one of the criticisms raised thing”,Mello comments. Incidentally, for The Juqueri, in Franco at the 1st Symposium of the IINN, in him, it was possible for the IINN enter- 2005.”The comment is by Luiz Eugênio prise to happen in Natal also because, da Rocha, São Paulo, Mello, pro-rector for postgraduate stud- some 30 years ago, a neuroscience group ies at the Federal University of São Paulo was set up at UFRN, led by Elisaldo Car- tried to be at the (Unifesp) and a specialist in neurophys- lini, from Unifesp. Without that, it could iology, with respected contributions in have been, as he understands it, any oth- outset a cutting edge the area of epilepsy. Mello, until recent- er city. Actually, behind the disputes and research center ly a scientific advisor to FAPESP,makes jealousies that are understandable in the clear his admiration for the work of university community, there seems to be Nicolelis, whom he classifies as “a bril- a certain fear relating to the scarcity of liant scientist, at the forefront of modern funds for research in Brazil.“As resources science that advances towards the area of are finite, Nicolelis’s group is well con- application”.And he admits that now the nected politically and very competent quest for interaction of the team with scientifically, there really is a certain fear other Brazilian scientists is expanding. So in the air when an enterprise vaunted as much so that he himself is taking part collective proves to be centralized in the in a project of cooperation with the IINN process of defining who goes there.” coordinated by Iván Izquierdo, of the What perhaps few may know is that Pontifical Catholic University of Rio Sidarta considers himself, not without Grande do Sul (PUC-RS), which also in- reason, as co-responsible for the idea of volves the group of Marco Antonio Máx- the institute. And Nicolelis leaves room imo Prado, from the Federal University for him to assume this condition. Ac- of Minas Gerais (UFMG). cordingly, to the question posed in his “I think that what stirred up the room in Natal about whether the institute community a lot at the first symposium is a dream of Miguel Nicolelis with which was the fact that the group presented it- he has contaminated many people, Sidar- ta replies that, in actual fact, it is not quite like that.“This dream begins in Juqueri in the 1920s or 1930s. Juqueri, in Fran- co da Rocha, São Paulo, tried at the start to be a cutting edge research center, and to this end brought together neurosci- entists, doctors with a psychoanalytic in- fluence...As an undergraduate, I was giv- en this story by my neuroanatomy pro- fessor, Marcos Marcondes de Moura, who went so far as to be the director at Juqueri. He used to talk a lot about this, about the Juqueri’s research program for understanding mental illness, the brain bank etc. Both theoretically and experi- mentally, they had great ambitions”,says Sidarta.And his conclusion is that he was contaminated by Marcondes with the idea of doing cutting edge science in Brazil in this neurological area. “When I went to the United States, I had this idea in my head. And I went about passing it on. I passed it on to Cláudio Mello, who was also from Brasil- ia and was my supervisor at the Rocke- feller. Then we started to create a group of people inside the Rockefeller who

GIOVANNI SÉRGIO GIOVANNI were thinking about this idea. And that

28 ■ SPECIAL ISSUE NOV 2006/SEP 2007 ■ PESQUISA FAPESP 22-31_Neuroscience_132_Ing 12/11/07 19:31 Page 29 RITA SINIGAGLIA-COIMBRA/UNIFESP RITA Creator and creature: conceiver of the institute in Natal, Sidarta analyzes reached Torsten Wiesel, the President of research directed by the problems, and action of during the university, who was thrilled”,he de- not by the techniques. rodents’ sleep tails. When he got to know Nicolelis, in “It was a very romantic idea, even 1998, and became enthusiastic about his with access to the forest to study animals work and his methods, Sidarta talked to in the wild “,says Sidarta.Accordingly, at him about the idea of the institute. the beginning, Nicolelis’s help for the pro- “Miguel was also enchanted, but at ject was to lend his prestige to make it vi- the beginning he was very well estab- able.“However, he himself went on get- lished at Duke. He was certainly the ting more and more enchanted with the Brazilian neuroscientist with the great- idea, and at a certain moment really est impact worldwide, a full professor brought something new to the project: with an excellent laboratory, two in fact, giving it a social mission”,he says. So the with plenty of finance.”So his reaction, idea, until then merely a scientific one, according to Sidarta, was positive, he “with Miguel incorporated this other di- thought that the idea was very good. And mension. That was at the end of 2002, be- because of his political commitment (his ginning of 2003, in the small hours, soon biography includes his struggles as a mil- after Lula’s victory for the presidency”. itant for the re-democratization of the And with this, Sidarta goes on,“it comes country in his youth and his presence together with a wish to bring the ludic, amongst the founders of the Workers’ ethical, meritocratic and even disciplinary Party, the PT), he offered to help. At that values of science to society, within the moment, they were thinking about cre- view that knowledge really is a liberator”. ating a cutting edge institute, in a beau- But, Sidarta adds,“without the force of tiful place that would attract people from Nicolelis’s enterprising spirit, none of this all over the world, where they would do would have gone ahead”.

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n front of the computer in the area ulation of them. In second place, that that he occupies on the left of his this population does not always have the room, Nicolelis explains that the same elements, but their constitution implants used in the animals in the changes every moment, that is, certain experiments, made of tungsten and neurons are summoned at one moment resin, are 4 or 5 millimeters in for the task of moving an arm, and, lat- length, two millimeters of which er on, others, not the same ones, may be Iremain in the brain. He will soon show called on to repeat the task. That is why us the neuroengineering room of the you can have traces of motor behavior laboratory where the electrodes are built. in areas of the brain that, in principle, Actually, it is always problematic when have nothing to do with movement.“In something foreign is put into the body, other words, the system is distributed, with one part inside and the other out- flexible, and not rigid”,he sums up. Nev- side, because this facilitates infections. ertheless, he emphasizes,“the concept of But one of the laboratory’s monkeys has distributed code does not eliminate the now had the electrode in his brain for concept of specialization. One does ex- six years without any problem. Never- clude the other”. theless, as you have to think of the fu- One proposal that all this raises is ture, engineers connected to several re- that the human brain perhaps has mil- search groups are working on the de- lions of neurons like a sort of potential velopment of wireless implants, in more reservoir to meet, at any moment, the effective neuroprostheses, “and one of need for these cells to carry out each be- Japan’s main robotics laboratories, the havior. Moreover, in the absence of spe- ATR, has decided to participate in an in- cialized cells, others may handle the task. A principle that ternational effort to search for better This notion of populations of neu- robotic arms and a vest capable of work- rons as a functional unit of the brain Nicolelis has been ing like an exoskeleton”. sounds “very sensible and very intelli- The conversation turns to the im- gent” to neurologist Iván Izquierdo, postulating for portant experiments connected to who, just like Nicolelis, is among the years is that groups Parkinson’s disease, which have given most quoted Brazilians in scientific lit- Nicolelis good evidence that a principle erature.“It is obvious that, in some as- of neurons, and that he has been postulating for years pects, the cell is a unit, but not from this is right, that is, that populations of neu- functional point of view”,he says. Much not each , rons, and not a single neuron, constitute respected for his studies of the memory the functional units of the brain. On ac- and mechanism for its consolidation, constitute the count of these experiments, neurosur- Izquierdo is at this moment concluding functional units geons from Duke recently met neuro- an analysis of his collaboration with the surgeons from the Syrian-Lebanese group from the IINN, for studies in neu- of the brain Hospital, at a workshop in São Paulo, to rophysiology, neurochemistry and neu- train them in a technique with elec- ropharmacology in the aged.“We are trodes that gives more precise indica- awaiting funds from the National Coun- tions, in a much shorter time, about the cil for Scientific and Technological De- areas that have to be removed to prevent velopment (CNPq) and we are going to the disagreeable symptoms of the dis- work with an animal model: transgenic ease. As all this is done with the patient mice.”He says that he is rooting for the completely awake, it is also possible to institute in Natal to do well and to be observe the patient’s responses that lead able to transform itself into an impor- to completely unexpected results. tant center to attract scientists from the “For example, we now know that, south and center of the country. with only 300 cells, it is possible to pro- Luiz Eugênio Mello also finds the duce a complex motor behavior”,says idea of neuronal populations interesting. Nicolelis. Of course, he says, “a given “It seems to make sense, but it is difficult number of neurons are needed to sus- to have conclusive demonstrations of tain any behavior, but instead of thou- this, not least for the very question of sands, it is possible for hundreds to ac- floating populations.” He imagines a quit themselves of the task”.In actual fact, model where floating neurons exist, but in a simplified way, what Nicolelis has at the same time are related to a restrict- proposed is, first, that the functional unit ed, specialized and always active nucle- of the brain is not the neuron, but a pop- us. As to the real application of robotic

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arms and other prostheses, he says that he sees a lot of future “if we succeed in overcoming some obstacles”.For exam- ple, if the implant is put totally inside the head, to prevent infections. If it can be ac- tivated without a wire,“with radio waves, for example, as we are trying to do”. Miguel Nicolelis shows an optimistic video about the institute, very close to the River Potengi, a tributary of the Jun- diaí. When asked why in Natal, he replies “because if we manage to do it there, it becomes clear that institutes like this can be installed anywhere in Brazil”.On the walls near his computer, there are many magazine covers, from The Journal of Neuroscience to IstoÉ (a weekly news magazine in Brazil), from the most spe- cialized, scientific ones, to the most gen- eral. On the walk across the campus to reach the other laboratory, in the midst of the now intense cold at the end of the afternoon, he talks about the book, more for laymen, about the history of his ex- periments, that he needs to finish for publication at the beginning of 2008, and of another two, more scientific.“What I want is to present a more comprehen- sive theory about the interaction of the brain with the technology that our cul- ture is creating. That may perhaps help to explain a series of phenomena that are not restricted to one brain, but relate to multiple interacting. And I advo- cate that perhaps some social behavior may be defined in the likeness and sim- ilarity of how brains naturally work.”

RITA SINIGAGLIA-COIMBRA/UNIFESP RITA It is a daring idea. About investments Floating populations: in Duke, Nicolelis says that about US$ distinct groups of nerve 40 million is invested in his two labora- cells may control one and tories. And in Natal? Certainly, the fig- the same action at ure of the originally estimated US$ 25 different moments million has now passed. And, running one of the 20 international groups in cutting edge neuroscience, he dreams of a virtual institute of the brain, integrat- ed by many units scattered all over the world, a horizontal Science produced in collaboration, independent of geography, based on the interaction of talents. A sort of archipela- go of knowledge, combating the pover- ty around it – the neolithic misery, as Sidarta says. He dreams of other re- search institutes in the Northeast. Real- ly dreaming, according to Sidarta’s re- search hypothesis, may perhaps be to simulate possible futures based on a re- membered past. ■

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