It's obvious how much respect Boyden has for his collaborators. Speaking to a standing-room-only lecture hall lined with dozens of students and faculty members, he spent the last minutes of his presentation reading off the names of students, post-doctoral fellows, collaborating groups and funding sources from a projected slide that listed even more of them. Then, he looked to the crowd and, almost in a whisper, said, "Thanks."
The idea that you could silence or activate neurons with light is a powerful one in combination with the tools that Boyden and Forest are working on together.
The two met at a social event at the MIT Museum while Forest was working on his Ph.D. at MIT. At that time, Forest was developing an instrument for genetic analysis involving thousands of glass tubes. Boyden told him about his own work in neuroscience, and about a problem that involved glass tubes for measuring neurons.
Forest didn't know anything about neuroscience, but he and colleagues "had a lot of expertise in how to build great devices," Boyden said.
The two researchers realized they could combine forces by creating a bundle of glass tubes, similar to what was being used for DNA analysis, for recording the electrical activity of individual neurons.
Neuroscientists often use mice, which have brains that structurally resemble those of humans, to test new technologies. Mice were the subjects of their first tests.
"We had no idea what we were doing at first," Forest said. "We went from a bundle back to one tube. We got that to work after three years of trial and error."
Those years paid off. Boyden and Forest, working with Forest's graduate student Suhasa Kodandaramaiah, developed a robotic system to record activity of a single neuron in the living brain using a tiny glass tube. The general technique, which has been around for about 30 years, is called "patch clamping," but this is the first time it has been fully automated through the assistance of a robot. The researchers have demonstrated the effectiveness of this technique in living mice, both awake and asleep.
Recording the neurons
Scientists know that the tube -- the "micropipette" -- has hit a neuron by measuring the electrical resistance between the tube and the brain. Resistance increases dramatically when the small needle bumps up against a neuron, as the tube forms a tight seal with the nerve cell.
"At that point, neuroscientists get very excited because you have the ability to hear the electrical activity of that single cell," Forest said. "Despite all the firing of millions of neurons in the neighborhood, once I form that seal, I can hear that one with exquisite sensitivity and precision."
There are only about a dozen of the automated patch-clamping robots in the world, but it's not Boyden and Forest's intention to keep them a secret. On the contrary, they've posted the complete plans for the robot on the Internet so anyone can download them and create their own.
"I would argue, if you really understand how the mind computes your thoughts and emotions -- things like sharing credit, teaching and doing good for humanity become natural," Boyden said.
The researchers are also working on a scaled-down version that would cost less and be more portable. They have spun off an Atlanta-based start-up company called Neuromatic Devices to sell the finished products, but neither holds equity in it.
Optogenetics can be combined with automatic patch clamping to identify neurons of interest and then measure their activity. The robot could also perform single-cell surgery.
Forest's group has already used the robot idea to simultaneously record intracellular activity from more neurons than anyone else -- only three, surprisingly -- in a live mouse. The Brain Activity Map's ambitions involve interceullar recordings thousands to millions of neurons at once.
When compared that way, the current neural recording technology is like a steam engine, while we need a rocket ship, Forest said.
"We've got a lot of work to do, and our hope is that this just plants some initial seeds towards that endeavor," he said.
One of the people e-mailing Boyden after The New York Times story was George Church, who has published research with him in the past. Church was one of the leading figures of the Human Genome Project, and a current backer of the Brain Activity Map.
Optogenetics, combined with high-density optical fiber arrays, could be a promising tool in the quest to map the brain, Church said. In other words, researchers can then use optic fibers to manipulate multiple neurons that activate in response to light. High-density optical fiber arrays would offer more, and thinner, probes for neuronal exploration than bulky electrodes.
Boyden and colleagues are also working on three-dimensional brain interfaces, manufactured in a way similar to computer chips. Rather than having computer circuitry on them, they have dense electrodes that would allow research to pick up on the activity of many neurons at once.
The data from recording so many neurons will require a huge amount of computer storage; for recording the entire brain at once, it would be mind-boggling.
"Most of neuroscience has gone on with people studying one part of the brain at a time," said Georgia Tech's Stanley. "Here's somebody's lab over here that studies this part of the brain, there's somebody's over there that studies that part of the brain. Putting it all together is really a tough problem."
Controlling his own brain
People don't like to talk about enhancing the brain, Boyden said; it makes people uneasy to think about designing or engineering a way to sharpen our minds. Yet plenty of people take pharmaceuticals -- sometimes without a prescription -- to help themselves focus or be less anxious, and caffeine and alcohol have been around for centuries.
"I think the most important thing is for humanity to openly discuss this topic," he said. "If we can discuss it, and we also can talk about side effects, should we maybe try to design more optimized versions of things?"
Enhancing his own brain was something Boyden thought about long before he became a neuroscientist.
At 18, he was taking six courses per term, all graduate-level. Feeling overloaded, and also curious about what it would be like to take a drug that focuses the mind, he went to the campus psychiatrist and got a prescription for Ritalin. He doesn't remember anyone telling him to just take fewer classes.
The drug did make him focus, a lot. He took one pill when he woke up and another just before plasma physics class, "so I don't remember much from that term except for plasma physics," he said.
But after a couple of months he stopped taking the Ritalin. He's not clear on whether the drug altered him permanently, or whether he just learned to focus better, skills for "how to simulate some of those processes in my mind."
Academically, Boyden never slowed down. On his 25-page resume, he lists perfect, or more-than-perfect, GPAs throughout high school, college and graduate school. At Stanford, he met his now-wife, neuroscientist Xue Han. They have published research together and are raising two young children. His "spare time" goes to his family.
In the last six years, he's found something new to calm himself and concentrate: meditation.
He meditates every day when he wakes up, incorporating a structure called "internal family systems," which involves looking at all the drives, thoughts and desires in your mind.
"By showing compassion for them, you can get them to become less polarized and work with them and negotiate between them and it's very powerful," Boyden said.
It takes him only a couple of minutes to get into a meditative state, which calms him and helps him analyze and address anxious thoughts.
I was surprised when he said he didn't know anything about the neuroscience behind meditation, which is a hot topic among other researchers, nor did he care about it as far as his own practice.
"I think that people should be careful about the need to see something in the brain to justify its worth," he said. "If you don't see anything in the brain, that might just mean the resolution of our brain (scans) just isn't good enough yet."
You can tell Boyden thinks a lot, for his own curiosity, and his vibe is more "grad student"-like than professorial. His frizzy beard resembles the thin branch-like connections between neurons that he's talking about. Every time he runs his hand through his curly brown hair, it falls down in a different unkempt way.