Ed Boyden and Optogenetics: The Future of Neuroscience

Solving Life's Eternal Questions With Neuroscience

Eric J. Topol, MD: Hello. This is Eric Topol, editor-in-chief of Medscape. I'm delighted to visit with Ed Boyden, from the McGovern Institute of Brain Research and the Massachusetts Institute of Technology (MIT) Media Lab. It's great to have you here, Ed.

Ed Boyden, PhD: It's great to be here.

Dr Topol: This is a pretty remarkable story. You're very young. At 37, you have accomplished so much. Let's talk about your background between MIT and Stanford. Tell me about your education.

Dr Boyden: I trained as an engineer and physicist. I wanted to make things to solve problems. I was also very philosophical and wanted to solve problems that would tell us about what it means to be human, the meaning of life—these eternal questions. About 20 years ago, I decided to go into neuroscience. I went to the Stanford PhD program. I hadn't taken a biology class since high school. I sometimes call it "strategic ignorance." It was good because I could bring ideas from other fields. I started thinking of ways that we could build technology and help us fix the brain. About 10 years ago, I went back to MIT and started a group to put it all together—engineering, science, and especially the focus on the brain. How do we solve these longstanding mysteries?

Dr Topol: You trained with Karl Deisseroth at Stanford.

Dr Boyden: Yes. We started working together when we were both students, actually. We met when he was finishing medical school and I was just starting the PhD program. We were both in Richard Tsien's group. That's when we started thinking up the optogenetic tools for solving the causality problem to activate neurons. We published our first paper together before I finished my PhD, working with Richard Tsien and Jennifer Raymond on motor learning. Afterwards, I did a brief post-doc with him and Mark Schnitzer, working on optics and the brain very broadly.

Optogenetics: Going Mainstream

Dr Topol: The Medscape community doesn't necessarily keep up with optogenetics—where it is and where it's going. Can you give us a thumbnail of this field? It's obviously one of the hottest topics in the life sciences.

Dr Boyden: Karl and I started brainstorming in early 2000 about how we would control the brain. You can try to fix the brain. More than a billion people around the world have some kind of brain disorder. As the population ages, Alzheimer's, stroke, epilepsy, and Parkinson's—the numbers are increasing. For many of these diseases, there are no cures. Treatments are partial and have many side effects.

We decided to try to figure out whether we could control the brain very precisely. What could be more precise than light? But there's a problem: The brain doesn't really respond to light. We brainstormed all sorts of ways to equip brain cells to make them light-sensitive. It turns out that the natural world solves the problem for us. All over the tree of life are molecules that are essentially photosynthetic. They convert light into electrical signaling. Brain cells compute with electrical signals. If we can put those molecules in and shine light on them, we can turn on neurons in the brain, in a very precise, digital way.

Dr Topol: At first it was a research tool to understand the brain dynamics.

Dr Boyden: That's right. Hundreds of groups have been using this to do basic neuroscience, to understand what causes a memory to form or an emotion to start. One of my favorite studies—because it's also an ethical and philosophical question—was done by a group at Cal Tech.^[1] They found a tiny set of cells deep in the brain, which, if illuminated and activated, trigger aggression or violence. They could pinpoint a site in the brain that triggers a complex behavior. It's mind-blowing.

In recent years, people have been trying to pinpoint patterns of activity in the brain that could help cure or at least treat the symptoms of brain diseases. People are now trying to figure out what parts of the brain must be turned off to shut down an epileptic seizure. People are trying to figure out what part of the brain you would need to stimulate to cancel the tremor of Parkinson's disease. Recently, I was part of a study,^[2] led by Professor Li-Huei Tsai at MIT, in which we found a pattern of activity in the brain that, if driven, seems to be able to clean up the amyloid plaques and other hallmarks of Alzheimer's disease.

Dr Topol: That was pretty exciting to hear about. Historically, the medical world and researchers have relied on functional MRI (fMRI). Now there's an entirely different way to map the brain functionally. How do you compare these two different tools?

Dr Boyden: fMRI and related technologies are fantastic. They're noninvasive, you can use them on normal humans, and they do not cause side effects. But the resolution isn't very good. When you see little voxels or blobs in the fMRI studies, those actually contains hundreds of thousands to millions of brain cells. We know from basic neuroscience that two brain cells next to each other can be doing completely different things.

The other thing about fMRI is that it's indirect. It's a measure of blood flow. The time scales over which you can measure fMRI are tens of seconds, but thoughts and feelings can change within fractions of a second. Even though optogenetics is a process that requires genes and light and other things that are difficult to use in humans, the temporal and special precision is extremely good.

Dr Topol: That's a very important distinction, being able to zoom in like that on an actual cell. Is "optogenetics" in the dictionary? Has it made it there yet?

Dr Boyden: Certainly in scientific realms, it is acceptable.

Dr Topol: Only this year, "microbiome," "epigenome," and "CRISPR" got in. The New Yorker had a big profile on optogenetics. That's mainstream, in the New Yorker.

Putting Opsins to Work in Human Disease

Dr Boyden: When something starts to have a direct impact on human health, that's when it starts to become part of the broader culture. There are a couple of companies that have already begun, or are about to begin, clinical trials in humans.

Dr Topol: What are these clinical applications?

Dr Boyden: Millions of people around the world suffer from forms of blindness in which the photoreceptors—the light-sensing cells in the eye—have died off. Retinitis pigmentosa is one of these diseases that affects several million people. If people can no longer sense light, it's very difficult to help them see again. Three different companies are trying to figure out if you can restore the sense of light by taking these light-sensitive molecules that Karl and I have been working on developing, and putting them into the blind eye and converting it to a virtual camera. If you could do that, you could help the eye image the world again. One company has already begun human trials in Texas. Another company in France is a little bit behind, but they have a more modern molecule. A third company is very interested in building computational devices that can pre-process the visual world, project onto the optogenetically sensitized eye, and streamline information flows that tell you more about the world.

Dr Topol: That's extraordinary. Have any patients with retinitis pigmentosa been treated?

Dr Boyden: A phase 1 safety trial has begun with a company called RetroSense. They are working in Texas. GenSight is in Paris. I believe they are completing their nonhuman primate trials now.

Dr Topol: Beyond this rare eye disorder, what other ways are we going to see optogenetics be tested in man for other indications?

Dr Boyden: A big question is, will optogenetics be best for studying the brain? Then, when you understand what's wrong, you devise a drug or noninvasive classical electrical stimulation method. For direct use, there is one big question that everybody is waiting for the answer to. The optogenetic molecules that we put into neurons are not human genes; they come from bacteria, algae, and other microbes.

Dr Topol: The opsins.

Dr Boyden: That's right. These are the opsins. One of the key questions is, how will the human body tolerate these molecules? They're foreign genes. Will there be an immune response? These molecules have never been in the human body before. How will the long-term toxicity profiles go? Many people are studying what will happen with these three retina companies. The eye has some degree of immune privilege; it's shielded from the classic immune system. Also, neurons are not dividing cells. If you put molecules into these neurons, they won't divide and lose the gene over time. This is one hope. If it goes well in the eye, the dam will burst open.

Dr Topol: It's exciting to get started in this sanctuary—the ideal spot—and see if that really takes hold.

Next Stop: Epilepsy and Movement Disorders

Dr Boyden: If it does take off, though, there are a couple of applications that people would like to see next. One area that several groups are working in is epilepsy. An epileptic seizure is uncontrolled electrical activity in a network of the brain. If you could turn off that network, that might be a very efficacious way of silencing a seizure. Right now, for drug-resistant epilepsy, many patients undergo neurosurgery to remove that part of the brain. If you could transiently silence that part of the brain, just for a second or two, and block the seizure, that would be less deleterious than having to remove a large part of the brain.

Dr Topol: Epilepsy has been a very neglected condition. Many people have intractable epilepsy. This would be extraordinary.

Dr Boyden: That's right, and not many new treatments have come out in recent years. The pharmacology of the treatments has stayed relatively the same for the past couple of decades.

Dr Topol: Hopefully we can do much better than deep brain stimulation. Besides epilepsy, what other indications are possible?

Dr Boyden: You brought up deep brain stimulation. There are many disorders for which deep brain stimulation is being explored. Parkinson's disease and movement disorders are the most widespread, with more than 100,000 patients already. In recent years, people have also started to look at very severe forms of autism, chronic pain, and depression. A big questions is, if you look at deep brain stimulation for Parkinson's and movement disorders, which is one of the largest patient populations, many people have cognitive or other kinds of side effects.

Ten years ago, a study^[3] came out showing that many people with implanted deep brain stimulators became more impulsive. We might need to make the precision higher-quality. What if you could actually stimulate a subset of the cells and only capture the cells that are directly contributing to the movement disorder? All sorts of pathways are always crossing in the brain. Isolating a subpopulation might help make the treatment better and the side effects fewer.

Dr Topol: That's a really good point—the idea of being able to accomplish fine mapping rather than the way we do it today, which is somewhat crude. That could have a big benefit. It's an exciting theoretical advantage.

Making Science Cool Again

Dr Topol: You won the Breakthrough Prize.

Dr Boyden: Karl and I shared the Breakthrough Prize in Life Sciences in 2016.

Dr Topol: Did you have any idea that you were going to get the call for this?

Dr Boyden: It came out of the blue. Also, I was a lot younger than many of the people who had won it in the past.

Dr Topol: You set a new record. How were you informed that you were going to win what is the American version of the "nouveau Nobel Prize," for which Yuri Milner and Mark Zuckerberg and your colleagues put together $3 million? Is it still $3 million?

Dr Boyden: That's right. They wanted to make a prize that was big enough to make science cool. Yuri is very interested in making science part of culture again—moon landings and computers and all that stuff. Science used to be part of everyday discourse. Making science more relevant is one of his big missions.

Dr Topol: I have gotten to know Yuri and, of course, Mark; they're amazing people. This is pretty imaginative. It has been running for a few years. You took the world by storm, being such a young guy to receive this award. What was it like? Apparently, they have a very fancy award ceremony.

Dr Boyden: They did. Yes. I was notified on my cell phone one afternoon. I thought, who is that? It was quite surprising. They swore us all to secrecy. We couldn't even tell our kids. I could tell my wife but nobody else. Then, they had a televised award ceremony, which was held right next to the NASA campus in Mountain View, California. Celebrities, singers, actors and actresses, Internet zillionaires, and other people came. It was quite the to-do.

Dr Topol: Did they entertain or did they want to hobnob with these newly recognized scientists?

Dr Boyden: A few people were part of the ceremony. They gave speeches and awards. Many people just came to hang out. It was quite the event.

No Degree? No Problem

Dr Topol: What did you do with this unfound $3 million?

Dr Boyden: After the obvious things are taken care of, like saving money for college and all of that, I started thinking about what we could do on purpose that the Media Lab—my academic home—did for me accidentally. Can we find—and facilitate—ideas that are misfits, people who don't quite fit in, or projects that can change the world but might seem a little bit wacky? I joined the MIT Media Lab in part because, at that time, many neuroscientists didn't think that tools for the brain were really going to work. Many of the engineers I talked to were asking, "Is there something more practical you can do, like work on something like cancer?" I joined the Media Lab in part because they were one of the few places that offered me a job, a place with a lot of great engineers, and the freedom to go in any disciplinary direction.

What I'm trying to do now is see whether we can help people pilot crazy projects that don't quite fit in. I started talking to people about the craziest things they could think of that wouldn't ever get a government grant or pass peer review—when other people have to tell you whether they think it's a good idea or not. There's something to be said for trying to hunt those ideas down. I'm trying to figure out how to evaluate and support these people. For example, there's a graduate student now at the MIT Media Lab who is doing the PhD program but never finished college. Can we find these people who are not traditionally credentialed scientists but who have that spark, that entrepreneurial drive? They may not have taken a traditional path, for whatever reason.

Dr Topol: Joi Ito, the head of the MIT Media Lab, does not have any [formal] education, is that right?

Dr Boyden: Yes. He dropped out of college. He became a DJ in the underground music scene in Chicago. Then he started the first Internet company in Japan, if I recall. Now he has become an Internet legend and has a second career as a nonprofit guru. He's on the board of the MacArthur Foundation and is director of the Media Lab.

Dr Topol: It's pretty amazing.

Dr Boyden: I bring that example up when people say, "You're going to take a graduate student who didn't finish college?" I respond that our director didn't finish college either.

Dr Topol: Exactly. He's a good model.

Dr Boyden: He did okay, right?

A Global Focus on the Brain

Dr Topol: I want to finish up with the BRAIN Initiative. There's worldwide interest that this precious organ has been understudied and is poorly understood. We have new tools, especially optogenetics, and this is getting a lot of funding from the National Institutes of Health. Where do you think the global and US BRAIN Initiative will go? Obviously, you're going to be a significant part of that.

Dr Boyden: It's interesting. Europe has a BRAIN Initiative; the United States has one, and China, Australia, Japan, and other countries have them or are planning them. Perhaps the most important impact is getting other scientific and engineering fields into the brain. There are so many different fields of engineering—chemistry, material science, robotics, and so forth. A lot of those experts are not working on the brain. Getting people excited about this is one of the biggest contributions that is happening. The brain is so complicated. You need serendipitous connections. You need outsiders. You need people who are going to connect the dots in novel ways to really contribute.

Dr Topol: Do you see some parallels to the Human Genome Project?

Dr Boyden: Great question. Yes and no. There is a parallel in that it is very technology-driven. The Human Genome Project, next-generation sequencing, and now genomics have become widespread. Prices have plummeted faster than Moore's law, even. That emphasis on technology is common with both the genome project and the brain project. There is a difference, however. The genome, in some ways, is a fundamental map: four letters, a string of them in a line. The brain is an open question: What's the fundamental description of the brain? Some people think we're going to find some simple rules that can explain thinking and feeling. Other people think it's going to be extremely complicated. In the artificial intelligence community, there's an area called "deep learning," where these algorithms are learning to pick out faces, classify cats versus dogs, or steer self-driving cars.

Dr Topol: They're even looking at skin lesions, x-rays, and MRIs—invading medicine in a big way.

Dr Boyden: When you look at these deep-learning maps, a lot of people say it is hard to understand how that artificial neural network learned it. The information is distributed in complex patterns. In some ways, our role is to build the tools to help us get as much understanding of the brain as possible so that we can build better computational algorithms, understand more about the human mind, and pinpoint the causes of brain diseases.

I think we're experiencing a sea change in the neurotechnology industry. Many of the neurotech companies in the past have struggled; it's a tough business. You can do something using the best engineering and it can still fail. The failure rate is high. Just in the past couple of years we've started to see investment in neurotech companies that are trying to do a lot of the fundamental science. They're going to try to bring together tools that are going to work pretty well because they're working at the natural scale of the brain.

One company, Kernel, just raised $100 million. Bryan Johnson is the CEO. I cofounded a company to commercialize the strategy for mapping the brain by using this baby diaper–like polymer to expand brain circuits so we can map them. We're finding that investment, business, science, and medicine have started to converge. What we might see in the coming decade is similar to what we saw in the past decade with genomics, and brain technology is going to explode, potentially.

Dr Topol: I hope so. We need to accelerate. There's so much at risk.

Dr Boyden: If we can build a sustainable neurotechnology ecosystem, I think that will bring a lot of benefit to human health.

Dr Topol: That's fantastic. We're relying on you to keep our brains healthy in the years ahead. You have been phenomenally successful at such a young age. Just think about 10 to 20 years from now—the impact that you and your colleagues will have in the field of optogenetics. Thank you so much for joining us. I would love to talk to you for hours on end. I hope to do that.

Thank you all at Medscape for joining this conversation with Ed Boyden. We will be following his career in this discipline of optogenetics and the BRAIN Initiative with great interest.