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Interview

Miguel Nicolelis: The man of multiple connections

A worldwide point of reference in neuroscience, restless Miguel Nicolelis, a citizen of São Paulo who has been living for over 15 years in the United States, is getting ready to enjoy his first sabbatical year. It will be quite a year. And the program for the next few months is now ready. He is going to spend a bit of time in Natal in the state of Rio Grande do Norte, by the seaside. Stay a few days in Lausanne, in Switzerland. A quick visit to São Paulo. And, when he feels homesick, go back to North Carolina, the state that is home to Duke University, where he heads up a laboratory with over 30 subordinates and a budget of a few tens of millions of dollars. Nobody thinks that Nicolelis is going to all these places as on an outing, although the stay in the São Paulo capital is always an opportunity to visit his parents and, if possible, see live a game with the Palmeiras club, one of his passions. 45 years old, the neuroscientist took a sabbatical year to have more time to work for his projects, in particular the construction of the Natal Neurosciences Institute. “I’m going to stay on the United States, Brazil and Switzerland air shuttle”, says the researcher, the father of three boys and married to physician Laura, a sort of administration manager of her husband’s ventures. In the land of watches and chocolate, the Brazilian, at the request of the Helvetians, is going to set up a new neuroscience center.

In this interview, granted during a recent trip to São Paulo, Nicolelis talks of the beginning of his career, still in Brazil, of the move to the United States, and of the progress of his researches, which have opened up the way for the creation of modern brain-machine interfaces. In the near future, these devices, driven by signals taken from patient’s own brain, may make it possible for handicapped people to move about with the assistance of robots. “We want the first human being to benefit from this technology to be a Brazilian”, he explains.

When did you begin to think about being a researcher?
It was after finishing the third year at the College of Medicine of the University of São Paulo (FM/USP), where I was sports director of the students’ club. I wanted to do something different, and not traditional medicine. I liked medicine, I still do, but I didn’t find the day-to-day of the clinical part as exciting as I had imagined. Then I began to look for a job in research. I went to talk to Professor César Timo-Iaria [a neurophysiologist who was working in the Biomedical Sciences Institute (ICB) at USP], who died recently and was my great mentor. And I asked Fapesp for a scientific initiation scholarship to work with computing. It was 1982, and the first generation of personal computers was arriving in Brazil. I was interested in epidemiology, in mathematical models for bacterial interaction. But I already had a very great curiosity of thinking of the brain as a large computer. The more I studied computing, the more I realized that the really interesting thing was to study the brain. When I finished college, in 1984, I was one of the two pupils of my class that opted not to take the residency exam. I went straight to doing a doctorate.

What was the doctorate about?
It was a strange thesis. Half of it was a computing project, analyzing neural connections. At the end of the doctorate, I reached the conclusion that neuroscience was in a dilemma. You could no longer look at just one neuron a time. You had to look to see various at the same time. That was the feeling I had reading all the scientific literature of the area. One advantage of being in Brazil was that, if there were difficulties in doing experimental things, it was possible to do tons of reading. There was time for that.

What did you do afterwards?
I finished the thesis in 1988 and began to look for some place in the world where there was someone who had at least an idea similar to mine.  After talking to Dr. César, I began writing to loads of people. I think that I received about 40 rejection letters. That was the rule. I suddenly I found in Science magazine two interesting advertisements. One was by a guy from Yale University, Gordon Shepherd, and the other by John Chapin, of Hahnemann University. They both accepted me, but I ended up going to Hahnemann. Yale wanted me to do something more traditional, interesting, but it really wasn’t my dream. John, from Hahnemann, a small university from Philadelphia, had the same idea as I did. He arrived at the conclusion that this really was the way, to record hundreds of nerve cells at the same time. John asked me to go there and do an interview, and I went. And, at the end of the day, he offered me a postdoctoral place at the university. Three months afterwards, I went to Philadelphia. Years later, after my departure from Hahnemann, this university was purchased, changed profile, and today is part of what is called the MCP (Medical College of Pennsylvania-Hahnemann University). But, for a period, it invested heavily in neuroscience and put a lot of money into the area.

What was life like at Hahnemann?
For six months, I left my family in Brazil, my wife Laura and my first son, Pedro, who was six months old. I had only a postdoctoral scholarship from FAPESP (I was only hired  by the university later). It was crazy. I arrived alone in a different world and was learning to speak English. But I was always treated very well. To have been first to a small place, without the pressure of Yale or Harvard, was great. After all, it wasn’t a place where it was expected of you to do something important right away. But, for me, failure wasn’t an option. Either I made good, got it right, or I wasn’t going to get any chance of doing what I wanted to in Brazil. It was all or nothing.

But was it good to do research there?
It was a paradise. John opened the door of a laboratory, which was already one of the cutting edge centers in neurophysiology in the world, and told me “it’s yours”. He put a Ferrari in my hands and said “learn to drive”. That’s how it is in America. The boss doesn’t keep on top of you the whole day long. He wants results, but the freedom is total. He gives you the means, he gives everything, but the deal is the following: “Get on with it, my friend”. And that is exactly what John did. I can only get to work this way. Here in Brazil, in Dr. César’s laboratory, I had this. But at USP, at the time, it wasn’t possible to have this.

Why?
The positions were much more hierarchical and fixed. I had a boss in pathology at USP who was a very tough guy. You had to do it his way or you were out. There was no alternative. You couldn’t question anything. In America, a student at High School queries what I say. And he is right to query. Just because I say it doesn’t mean to say it’s the truth. You can’t question the boss here. He is God. This posture kills science. It’s not just the lack of money that kills science. Anyone who is in research and can’t manage to get autonomy is going to become a technician. He’s not going to become a head researcher. At Hahnemann, I also learnt to manage my time. I had to divide my day between doing experiments and reading. I can say that I did a course in neuroscience in three years like I would never have done in my life. It was all there: scientific literature, books and the Internet, which was beginning to appear. I think that I have never read so much in my life as from 1989 to 1993.

What did you learn in this period?
I knew what was happening in neuroscience from back to front. I knew everybody who was in the vanguard of the area. It was when I discovered what there was above the clouds. It’s not reaching the clouds, but seeing what is above, what the horizon is. Discovering what the fundamental question is that has to be asked in your area. That is very difficult. It took four, five years for me to get to have an idea.

And what was your idea?
I was interested in understanding the laws of physiology that govern the interaction between large populations of neurons. If we understand this, we will understand everything. We will be able to understand how the brain works, explain conscience, and even how neurological diseases destroy this notion. This is the Holy Grail of neuroscience. Today, I feel that we are very close to creating a unifying theory that brings all this together onto a single mechanistic basis.

How did you get transferred from Hahnemann to Duke University?
One day, a guy appeared at Hahnemann who was the head of a new neurobiology department at Duke, Dale Purvis, who was famous, and I knew him by name. Dale had heard about my work because I had given a talk, one of the first of my life, at a congress, and because a great friend of his knew one of the professors at Hahnemann who was working with me. He was there to give a talk and said he wanted to chat with me. To my surprise, the guy spent three hours with me, looking at my experiments. One month afterwards, I got an invitation from him to give a talk at Duke. I had never given a talk outside a congress, those where you are invited to speak. I thought it was great. I gave my talk at Duke and spent the day talking to this professor.

Were you already making references to Brazilian soccer in your talks in those days?
Yes. But we hadn’t yet won the 1994 Cup. I gave the talk and spent the whole day in conversation with loads of professors from the department. The last meeting of the day was with Dale. Then he told me that people had liked my talk very much and that he was there bringing everyone’s impressions. I thought it very odd. But Dale carried on and said that the impressions were excellent and offered me a job.

Was there an evaluation process?
There was. It’s what they call a job talk or job interview. But they didn’t tell me anything about this because they thought I would be nervous, that I would try to impress people in the interview. And they want to see me being natural. When the day ended, I had an offer of a job at one of the largest research departments in the country with things that I didn’t even know existed. For example: when you get a job in America, they give you a budget for you to create your laboratory. A quantity of money I had never seen before in my life. They give so many years of support. They pay for your move and all you need to install yourself.

They make a big investment in the person.
Tremendous. They select people well. They don’t hire by competitive examination. There’s none of that examining board. They sweep the country in search of the guy that is a perfect match for what they want. That is done by looking at the candidate’s résumé and production, asking for a letter of recommendation from people that interact with the candidate, and by interviewing him, of course. That’s how it works. And, by the way, it works very well.  When I arrived at Duke, I and Laura, who immediately became my laboratory manager, there was just the floor of the rooms we occupied, an office, and a lot of money for equipment. And nothing else.  I like to say that setting up a laboratory is like creating a baker’s shop. You are a businessman. You have to do everything, go after pupils, post-docs, technicians, equipment, laboratory animals. And get money. The university invests in you, makes a sort of loan, but wants a return. The pressure is very great. I didn’t know what it was like. In the beginning, I took some knocks. At Hahnemann, I was in almost a family environment, with six people in my laboratory.

What was this pressure like?
You spend six years being continuously reviewed and evaluated. After this time, either you stay there, or they send you away.

Is there any making of demands, in terms of publishing scientific articles?
Of course. They demand publication. And they always ask what you are doing and what your ideas are. You routinely give seminars for the university. When I arrived at Duke, I really was a cucaracha. The guys would ask me: “Did you study at the University of São Paulo? Whereabouts in California is it? Near to San José, Santa Barbara? Where is São Paulo?” I would say that it was further south. It’s true. I had to face up to that.

Was it as Duke that the implants of electrodes in animals began?
No. It was before, still at Hahnemann. My idea was to develop a new surgical technique and a method that, from the start, would make it possible to record multiple places in the brain. I did this first in rats. As the space in the animals’ head is very small, I had to create techniques to put multiple connectors in the rodents. At that time, the connectors were big. Today, we have microconnectors. When I left Hahnemann, I had already done experiments that yielded an article for Science. But it was at Duke, after 1995, when I published my second article in the magazine, that my work exploded. In this article, we showed for the first time the full record of a sensory nerve, from the first neuron in the trigeminal ganglion to the cortex. No one had ever seen this image. It’s like aiming a telescope at a galaxy never observed before.

What was the repercussion of this work?
I think that, to this date, it is the work of mine most cited in the scientific literature. It was a revolution. It showed that the dynamics of the brain circuit as a whole could not be foreseen by the records at a single place. And that, in actual fact, all the components of the circuit contain information from the other structures. That is to say, all the structures are connected, and with multiple fibers. One piece of information that appears in one structure is rapidly disseminated to the others of the circuit. Instead of being a hierarchical process, where each structure performs a function, it is a shared process. All the structures have shared functions. It was a work that opened the doors for me. Evidently, when we did something of this size, half of neuroscience said it was madness.

And the other half thought it was sensational.
The other half was flabbergasted, and began to invest in the area. But it was a very difficult period. My first pupil at the Duke laboratory was an American son of Pakistani parents, Asif Ghazanfar. As a joke, he and I used to call our laboratory a laboratory from nowhere. That was because the supervisor was Brazilian and the pupil was Pakistani [today, there are over 30 people in Nicolelis’s laboratory, 8 of them Brazilians]. Except that Asif was a scalawag – today he is a Princeton professor – who bought the dream. He helped me a lot. Our production was very large. But, in 1997, I realized that there was no point in remaining just in the tactile, sensory area, which is my specialty. To show that this concept of how the brain works was general and fundamental, we had to go to other areas. We had to have a visual, concrete demonstration of this idea. So we created a brain-machine interface.

What exactly were you thinking of?
At that moment, I still didn’t have any notion that this work was going to generate a possibility of clinical therapy. There was no way of foreseeing it. What I wanted was to demonstrate that it was possible to read electrical signals from the brain, extract a motor code, and use this signal to control a mechanical arm, which would reproduce a movement that the animal would make. This was the concept to be demonstrated. Going back to Hahnemann, still with John Chapin, when we did the first experiment on a rat, we saw that we were before something gigantic, much bigger than a simple demonstration of a theory. We really could be opening up a floodgate. And it really was that. Straight afterwards, I did the first work with monkeys, at Duke, and the animals managed to control a mechanical arm with a brain-machine interface. So the thing really exploded. There was a potential not only in basic research, which continues to be a hot area, but also in terms of clinical applications.

What are the prospects for applying the brain-machine interface in man?
Some two years ago, we tested the interface on 11 human patients, while they were being submitted to a surgery to alleviate the symptoms of Parkinson’s disease. It worked well. We temporarily implanted 32 microelectrodes in a region of the brain and captured sufficient electrical activity to move a prosthesis. But there are various possibilities for applications. We have to invest in multiple directions at the same time, including in more basic research. After we demonstrated the potential of this approach, several research groups in the United States began to work in the area. But some people already want to make money with this, and that is an attitude that I abhor. There are two or three companies that are saying openly that it is not necessary to do more research, but just to put the implant, wires and all, into people. That’s madness. There are several questions for which we have no replies yet. How is the brain going to respond to an implant that lasts years? We, for example, have there in the United States two owl-monkeys that have been four years with the implant. The animals are well and the implant continues to work. We are publishing a work about this experiment.

Is one of the greatest problems of the brain-machine interface the miniaturization of all its components?
Yes, but we have miniaturized a good deal of what I used in the first experiment with human beings. Now, almost everything is on a chip, a little board smaller than a credit card, which in future, theoretically, the patient is going to carry on his belt, as if it were a cell phone. We are now implanting a series of equipment for six months in monkeys. It may not even be the version of the interface that is going to be used in a human being, but it is very close to it. It’s all wireless now. The signals captured in the brain are going to be transmitted by a radio wave. It all goes to this board, which sends the signals, like a cell phone, to the robot, which is alongside the patient.  Besides this, we have also begun to test an exoskeleton, a metal vest that we put onto the monkey for it to exercise on a treadmill.

What is this exoskeleton project?
It’s a complete garment, from head to foot, which would hold the handicapped person. Exoskeletons already exist, but they are very heavy and complicated, and nobody has ever thought of controlling them with signals coming from the brain. Actually, what already exists is a robot that walks, but that doesn’t follow a curve, nor stop when you want. That is to say, a quadriplegic person gets into a device and it’s the device that walks. My idea is to adapt this robot, which was created to be used on Mars, where an astronaut might not have the strength to walk, due to the wear and tear of the journey. Nobody doubts that we will be able take the signals from the brain necessary for controlling the joints of this robot. What nobody knows is how we are going to keep this person inside the exoskeleton. This is because when the robot walks, the balance is disturbed, and it no longer succeeds in maintaining the erect posture of when it is standing still. This is a great challenge for control, an engineering problem. In this situation, the brain is also going to have to provide balancing signals for the robot. And no one has ever done this.

The person has to relearn how to walk, except using a robot?
Precisely. And the robot has to relearn as well. Adaptive engineering will have to be created, adaptive models that learn like a child.  That is precisely the idea. It was this that led me to talk to researchers from Switzerland and Japan, where the gods of robotics in certain areas are. It was also this that made me have the idea of creating an international network of neuroscience institutes, with its headquarters in Switzerland, which the Natal project will be part of. Neuroscience has grown so much today that it’s almost in the same situation as physics 40 years back. It’s impossible to do something with an enormous impact in a single place. There has to be a group of people with the most diverse specialties, from wherever is necessary.

By the way, how did the idea of the Natal Neuroscience Institute arise?
It arose in 2002, from three Brazilians, me, Sidarta Ribeiro, from my team at Duke, and Cláudio Melo, from the Oregon Health and Science University. We arrived at the conclusion that Brazil had to invest in cutting edge science done within a different model, more agile, and with a social vision. The university model of Brazilian research is traditional, complicated, and is facing many problems. We wanted to create something like the Max Planck Institutes, in Germany, which form a network of institutes inside the country in vital areas.

Isn’t it a megalomaniac idea?
Of course. No doubt about it. But my grandmother always used to say, and I’m going to repeat it until I die, that to dream small and to dream big take the same time. Except the end product of the small dream is very small, compared with the big dream. That’s why it’s better to dream big. I don’t have the ambition to put this network into effect in two or three years. It’s a project for a generation, which is beginning now with the Natal Institute. This model does not exist anywhere. Science can be an agent for social, educational transformation and for providing clinical services. The brain is to do with sport, science, art, it’s a revolutionary thing. Today, this vision is not just mine. Other people in other countries have begun to look towards this idea as something overwhelming, in such a way the major part of the sizable resources today for the Natal project is coming from outside Brazil.

What are there in resources up to this moment?
First, we received some sources of funds from the federal government, coming from agreements with different ministries. Something between R$ 4.5 million and R$ 5.5 million. Part of the resources are already in Natal, part we are waiting to receive. But, suddenly, for example, we established an important partnership with the Syrio-Lebanese Hospital, of São Paulo, which is going to be part of this international network of institutes in neuroscience. The Syrio will be the network’s clinical centre par excellence, and, in compensation, made a donation of US$ 1 million for the social part of the project in Natal. I also managed to raise, there in the United States, research contacts for Brazil in the order of US$ 2 million for the next two or three years. A little while ago, we did a charity auction of works of art in São Paulo, and in one night we got R$ 350 thousand.  When I took the Natal project to the people in Switzerland, they told me the following. If I were to create a neuroscience institute in Lausanne and set up the center of the international neuroscience network there, they would help me to raise US$ 6 million for the Natal project. I accepted. Up until now, I think we have managed a total of US$ 10 million for Natal.

Is it all right with the plot of land in Macaíba, on the outskirts of Natal, where the headquarters of the institute is going to work?
It is, and we now have another plot of land, donated by the municipality of Macaíba, where we are going to build the school and the mental health institute connected with the institute. But, before we start the works for the definitive headquarters of the project, alongside which a multisport complex will also be functioning, we have not stayed still. We decided to rent a building in Natal to house the institute’s first laboratories, as well as the first social component of our project, which will be classes in scientific education for the public of children. Sidarta is now setting himself up in Natal to begin to run the institute.

What will be the role of Natal and Brazil in this research network?
I want to do the final part of the clinical tests here, with the support of Duke. Why here? As soon as the Natal project started to move, we arrived at the conclusion that we would need a clinical center to work for this international network. In spite of Duke having a large-sized clinical center, we wanted to do this part of the clinical research in Brazil. We want to make history here. Hence the partnership with the Syrio. We want a Brazilian to be the first human being to benefit from this cutting edge technology and to walk and move his arms again.

How long will it take for this to be possible?
It’s difficult to foresee, but we plan to be in a condition to do this in the next three years. I can’t discard the hypothesis of someone being successful before us. Suddenly, a revolutionary discovery appears. But that’s our deadline. The important thing is that there should be a real benefit during the clinical tests. I want the first patients to be able at least to feel motor restoration and carry out tasks. A quadriplegic, for example, would use a robot to pick up a glass or a fork. Nobody is going to get out of bed walking straight off.

Will the Natal Institute be open to the participation of researchers from Brazilian universities?
The institute is a private project, but it is open to collaboration with everybody. I have been much sought after by a new generation of neuroscientists. I receive e-mail from all over Brazil. But the vision of the more senior generation of Brazilian scientists is very feudal. It thinks that territories are impenetrable. Each one has his own feud and does not want other feuds to appear, because that way there is more competition. To feel that this still exists in Brazil was a very great disappointment. I don’t need any feud in Brazil. That was never my intention. I never wanted to contend with Brazilian researchers for funds from the CNPq, FAPESP or Finep, not at all.

Do you feel that this was the predominant tone of the reaction to your project in Natal?
There was a totally exaggerated fear, particularly at the beginning of the project. If there was a great disappointment, it was to see that people in high places in the Brazilian scientific hierarchy have such a small mentality. This is human nature, and it has never influenced me. But the opposite also happened, the reaction of people who received me with enthusiasm.

What are the reactions like today?
I think that people don’t have a lot to say. At the beginning, they thought that the Natal Institute was a very fine utopia, but that I would throw the towel in as soon as I tasted Brazilian reality. But I didn’t chuck it. The attitude I have is the same that I had when I went to America: failing is unconceivable. It may take 20 years. I never said that I was going to do this in two, three or four years. But the words give up are not part of my vocabulary.

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