Brain gain. A proposed research effort to map brain activity could help make electrode arrays, such as the one shown, fi ner and more fl exible.

in action. “The biggest need in is to develop technologies that would allow us to record the activity of many, many in a circuit to understand how the circuit functions through that aggregated activity,” says Story Landis, director of the National Institute of Neurological Disorders and Stroke. “And we just don’t have the tools to do that.” Neuroscientists arguably can only crudely measure the activity of a brain now. They can turn to PET and MRI imaging that each detect “activation” of broad regions through proxies such as oxygen use, or they can measure the electrical activity of indi- vidual or small groups of neurons. How- ever, the brain’s most interesting functions, such as thought and perception, probably incorporate thousands to millions of neu- rons, says neuroscientist John Donoghue of Brown University, who has participated on March 3, 2013 in planning the new project. To understand “thought disorders” such as schizophrenia, he says, we need to know what level of cellu- lar activity produces thought. “Does it take 1000 cells? 10 million? 100 million?” NEUROSCIENCE In 2011, at a meeting of neuroscientists and nanoscientists in England sponsored by

Brain Project Draws Presidential the Kavli, Gatsby, and Allen foundations, a www.sciencemag.org handful of scientists proposed that the two Interest, but Mixed Reactions disciplines combine forces to develop tools to answer that question, by recording “every Shortly after President made for individual scientists, especially at a time action potential from every within a seemingly innocuous pitch for more brain when NIH faces a massive budget cut (see a circuit.” Some naysayers called the idea research in his State of the Union address last p. 1020). The Atlantic, for example, pub- “ridiculous,” says Rafael Yuste, a Columbia month, National Institutes of Health (NIH) lished online a series of negative tweets, University neuroscientist who has helped Director Francis Collins sent out a note to mainly from non-neuroscientists, decrying plan the BAM project. But George Church, Downloaded from his Twitter followers: “Obama mentions the the Brain Activity Map (BAM) proposal, the molecular geneticist #NIH Brain Activity Map in #SOTU.” including this one from biologist Michael in charge of the Personal Genome Project, Few paid heed, however, until a week Eisen: “someone has to go to congress and pointed out that nearly every objection had later when a front-page story in The New explain why basic research is so important, also been raised against the Human Genome York Times indicated that the mysterious not pander to them with big science crap.” Project. “The more questions people asked,” tweet referred to a soon-to-be announced Even some in the neuroscience commu- Yuste says, “the stronger the argument NIH-led effort rivaling the Human Genome nity expressed concern. “If this takes away became that this could be done.” Project in cost and ambition, one that from any of the R01s [individual investiga- After the meeting, Yuste, Church, and Obama planned to call for in his upcoming tor grants] that would normally be funded by three other scientists hashed out a white annual budget proposal. The initiative aimed the NIH, it would be bad,” says Eve Marder paper on their idea. Miyoung Chun, the vice to do no less than “build a comprehensive of Brandeis University in Waltham, Mas- president of science programs at the Kavli map of [the human brain’s] activity” within sachusetts, a former president of the Soci- Foundation, soon became its most vocal a decade, the newspaper reported. ety for Neuroscience, who had attended one and organized advocate, Yuste says. After The story stunned and excited many in of the early planning workshops for BAM. the group coined the name “Brain Activity the scientifi c community but angered and “Right now the community is already so Map” for the project, Chun sent the docu- worried others. Lacking any offi cial decla- strapped we’re at a breaking point.” ment to the Office of Science and Tech- ration of the project’s cost or how it would Whatever one’s initial reaction to the new nology Policy (OSTP) at the White House. be funded, some researchers bristled at the initiative, there is little doubt that research- Within a few months, Yuste says, they prospect of a large new federal initiative that ers, and potentially physicians, would ben- “made the rounds” in Washington, visiting

could take money from traditional grants efi t from better ways of observing the brain OSTP, NIH, the National Science Founda- PH.D./WWW.NEDSAHIN.COM SAHIN, T. NED OF COURTESY CREDIT:

1022 1 MARCH 2013 VOL 339 SCIENCE www.sciencemag.org Published by AAAS NEWS&ANALYSIS

tion, and the Defense Advanced Research the millisecond speed that neurons fi re— Projects Agency. OTHER BIG BETS ON THE BRAIN all the while making sure that the method In June 2012, the group published a paper doesn’t itself alter brain activity, he notes. in Neuron outlining how three areas of tech- Kleinfeld says he has concluded from some nological development could lead to a bet- rough calculations that such a feat isn’t ter understanding of brain function. First, physically achievable in more than a small they envisioned finer, more pliant micro- region of cortex. electrode arrays that mold seamlessly to Further confusion about the project stems brain tissue and record from larger groups from a discrepancy between its descrip- of neurons. Second, they proposed an effort tion in the Neuron paper, which focused on to advance the fi eld of optogenetics—which animal models, and the current iteration, has lately revolutionized neuroscience by which refl ects a “socially responsible,” more allowing researchers to manipulate neu- human-oriented version, Yuste says. During rons using light (Science, 15 December meetings with NIH, he explains, offi cials 2006, p. 1674)—by incorporating voltage- said, “This is good that you’re going to map sensitive, light-emitting particles such as • The Human Connectome Project: A the activity of every neuron in the brain, but quantum dots and nanodiamonds into neu- 5-year, $38.5 million project funded by how about solving schizophrenia? What is rons, allowing scientists to track and manipu- the National Institute of Mental Health this going to do for mankind?” At that point, late neuronal activity on a much larger scale. to map structural connections (above) in Yuste says the group invited researchers Finally, drawing on the growing field the brains of hundreds of healthy adults. with more practical links to patient care to known as synthetic biology, they expressed join the planning. In the updated version of • The Human Brain Project: A €1 billion interest in one day inserting artifi cial DNA- the project, research with humans will be European-led project to build a computer synthesizing enzymes into neurons so that model of the human brain over at least conducted in parallel with more basic sci- every time the neuron fired, the enzyme ence, says Donoghue. He hopes that BAM the next 10 years (Science, 11 November on March 3, 2013 would make an error in its DNA assembly, 2011, p. 748). will reveal how the brain encodes move- thus recording the cell’s activity through a ment, which would help him build better series of mistakes. Whether such molecules • The Allen Brain Atlases: Maps of gene brain-machine interfaces that allow para- could ever be used in humans, or how the expression in the brain. A mouse brain lyzed people to mentally operate robotic data they generate could be recovered is still atlas, completed in 2006, cost $41 arms more naturally. unknown, the authors said. million; a human atlas is under way. Still, don’t expect a complete human Such tools are far from being ready for brain activity map by 2025. For ethical human use, the scientists caution. Nonethe- and safety reasons, most of the techniques

less, they suggest that over 15 years the fi eld described in the group’s new proposal are www.sciencemag.org could ramp up from monitoring the equiva- might aid the effort, but only the Kavli decades away from being applicable to lent of the whole brain activity of the round- Foundation has so far made any public com- humans, Rubin says. Research proposed in worm Caenorhabditis elegans, which has mitment, stating it expects to contribute up the Neuron paper will largely focus on fl ies, 302 nerve cells, to up to a million nerve $4 million to $5 million per year of the total. worms, zebrafi sh, and mice, he says. cells—equivalent to the entire brain func- Gerald Rubin, executive director of Howard The most recent description of the project tion of a zebrafi sh or the Etruscan shrew, one Hughes Medical Institute’s Janelia Farm suggests establishing national “brain obser- of the world’s smallest mammals. Research Campus in Ashburn, Virginia, vatories” that would “provide access to new “There are people who may say this is says his facility has already spent more technology to all potential users, and serve Downloaded from not possible, that we are smoking some- than $150 million on research relevant to as a collaborative node for the BAM com- thing. But if you look back at the genome the Brain Activity Map over the past 6 years munity.” But it is impossible to tell how the project, a lot of people said it was crazy and and will continue to use its yearly budget of project will be administered at this point, says would never work. There are very few peo- $100 million along those lines. Ralph Greenspan, a systems neuroscientist ple saying that today,” says nanoscientist Beyond the budgetary issue, some at UC San Diego and one of the core scien- , director of the Lawrence researchers have questioned the realism of tists planning the initiative. Berkeley National Laboratory in California BAM’s stated goals. Partha Mitra, a neuro- Based on his experience with large and one of the project’s planners. scientist at Cold Spring Harbor Laboratory research efforts such as the Human Genome A big unknown is how much pursu- in New York, called several of its techno- Project, Greenspan says new dedicated fund- ing such an initiative would cost. The New logical proposals “science fiction.” And ing is needed to go ahead with BAM. “In no York Times reported that Yuste and others although he supports the project as a whole, sense is this something that should replace involved have suggested the cost would be “I fl inched when I read the phrase ‘every other basic research” like the connectome $300 million annually for a decade, compa- spike from every neuron,’ ” says David project (see box), he says. But that decision rable to the $3.8 billion spent on the Human Kleinfeld, a neuro physicist at the University is largely out of his hands, Greenspan adds. Genome Project, yet the researchers offered of California (UC), San Diego. Capturing “Our role was to bring it to the attention of no explanation for that cost estimate when pulses of scattered light from nanodiamonds people in Washington, who to our delight asked by Science. And OSTP and NIH have embedded deep in the brain’s intricately seemed to embrace it enthusiastically.” Now, so far declined to address the cost of the folded tissue would require inventing cam- he says, “they’ll do it the way they see fi t.” project and whether it would draw on exist- eras and microscopes that can record pho- –EMILY UNDERWOOD

CREDIT: THOMAS SCHULTZ/CREATIVE COMMONS THOMAS SCHULTZ/CREATIVE CREDIT: ing budgets or new money. Private money tons from all planes in three dimensions at With reporting by Jocelyn Kaiser and Robert F. Service.

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