Neuroscience Thinks Big Bring Them Together in a Unified View

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PERSPECTIVES

VIEWPOINT new computing technologies. Neuroscience is like the infant brain — it is flooded with data and theories but lacks the ability to Neuroscience thinks big bring them together in a unified view. We pin our hopes on more and more data with- (and collaboratively) out realizing that experiments can only give us a small fraction of what we need. The Eric R. Kandel, Henry Markram, Paul M. Matthews, Rafael Yuste and attempt to reconstruct the human brain as a computer model can provide a new focus Christof Koch for neuroscience and for clinical and tech- Abstract | Despite cash-strapped times for research, several ambitious collaborative nological research. It will help us to ‘clean neuroscience projects have attracted large amounts of funding and media up’ conflicting reports and teach us how to apply knowledge from animal studies to attention. In Europe, the Human Brain Project aims to develop a large-scale understanding the human brain. Ultimately, computer simulation of the brain, whereas in the United States, the Brain Activity it will allow us to discover the fundamental Map is working towards establishing a functional connectome of the entire brain, principles governing brain structure and and the Allen Institute for Brain Science has embarked upon a 10‑year project to function and to predictively reconstruct understand the mouse visual cortex (the MindScope project). US President Barack the brain from fragments of experimental data. Without this kind of understanding, Obama’s announcement of the BRAIN Initiative (Brain Research through Advancing we will continue to struggle to develop new Innovative Neurotechnologies Initiative) in April 2013 highlights the political treatments and brain-inspired computing commitment to neuroscience and is expected to further foster interdisciplinary technologies. collaborations, accelerate the development of new technologies and thus fuel much needed medical advances. In this Viewpoint article, five prominent Paul M. Matthews. The Human Brain neuroscientists explain the aims of the projects and how they are addressing some Project will engage a consortium of 80 neuroscience centres across Europe to aggregate of the questions (and criticisms) that have arisen. brain functional data on an unprecedented scale, use data-mining techniques to derive What are the (long-term) goals of these of learning, memory, emotion and even an understanding of the way the human projects? Why is now the right time to decision-making. These findings position brain is constructed and then apply what is invest in them? scientists, especially in the Brain Activity learned to revolutionize computing and to Map project, to be able to begin to tackle develop new approaches for the diagnosis Eric R. Kandel. The long-term goal of the overall organization of brain structure and treatment of brain disease. This is a these highly ambitious projects is to gain and function. hugely ambitious remit. A strength of this a better understanding of the anatomical, Second, in recent years, scientists have project is the focus on multilevel integra- molecular and circuit bases for the logical developed a range of new technological, tion. However, at this early stage, the project operations carried out by the human brain. molecular and computational tools that is more aspirational than scientifically well The Human Brain Project (see Human Brain allow for more efficient and accurate record- targeted. It emphasizes a massive scaling up Project), based in Europe and led by H.M., ing from many nerve cells at the same of activities in many areas of neuroscience aims to understand the human brain by time, for mapping of connections between rather than exhaustively exploring a specific simulating its functions through the use neurons in the brain, for correlating struc- question or innovation challenge. of supercomputers. The Brain Activity Map, ture and neural activity with function and The BRAIN Initiative (Brain Research with which I am more familiar, will be based for manipulating neural activity to test the through Advancing Innovative in the United States and coordinated by causal role of defined neuronal elements in Neurotechnologies Initiative; see BRAIN Francis Collins, Director of the US National behaviour. Initiative) is still more of a commitment Institutes of Health (NIH), and Story than a reality. The specific goals are not Landis and Tom Insel, Directors of the US Henry Markram. The Human Brain Project set but will be considered over 2013 by an National Institute of Neurological Disorders is building the foundations that we need to advisory committee to the US NIH Director. and Stroke (NINDS) and the US National reconstruct and simulate the human brain However, a vision for the BRAIN Initiative, Institute of Mental Health (NIMH), and its diseases, and to develop related com- which focused attention on the challenge respectively. puting technologies. This is terribly urgent. of developing tools able to describe activ- These projects may be early for the Today, we are failing to translate our rapidly ity across every cell in a functional unit to human brain, but it is a good time to improving knowledge of the brain into ben- characterize ‘emergent properties’, was set undertake these ambitious tasks in experi- efits for society. Very soon the cost of brain out in a 2012 Neuron paper1 from a group mental animals for two reasons. First, in disease will reach 10% of the world’s gross led by R.Y. Specific opportunities offered by both simple invertebrate animals, such as domestic product (GDP), yet the develop- voltage-sensitive optogenetic probes, wire- worms and flies, and in vertebrates, we ment of new treatments is grinding to a less (nano) electrophysiological sensors and have begun to understand how the brain halt. There is still a massive gap between the synthetic biology were highlighted. processes sensory information and how neuroscience laboratory and the clinic. In Why are these initiatives coming now? the brain initiates movements. We have the same way, we still do not know how to Politically, we need them to help real sci- also gained insight into the neural basis use our knowledge about the brain to build ence funding grow. They both emphasize

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The contributors The time is ripe now because of the Eric R. Kandel is University Professor at Columbia University, New York, USA, Fred Kavli Professor development of different areas of associated and Director at the Kavli Institute for Brain Science at Columbia University and a senior technologies, such as optogenetics, synthetic investigator at the Howard Hughes Medical Institute. A graduate of Harvard College, Cambridge, biology, nanotechnologies, microelectronics Massachusetts, USA, and New York University School of Medicine, New York, USA, he trained in and computational analysis of large-scale neurobiology at the US National Institutes of Health, Bethesda, Maryland, USA, and in psychiatry at datasets. Harvard Medical School. He joined the faculty of the College of Physicians and Surgeons at Columbia University in 1974 as the founding director of the Center for Neurobiology and Behavior. Christof Koch. To understand the cer- His research has been concerned with the molecular mechanisms of memory storage in Aplysia ebral cortex, we must bring all available californica and mice. More recently, he has studied mouse models of memory disorders and mental experimental, computational and theoreti- illness. Kandel’s work has been recognized with the Albert Lasker Award, the Heineken Award of cal approaches to focus on a single model the Netherlands, the Gairdner Award of Canada, the Harvey Prize and the Wolf Prize of Israel, the National Medal of Science USA and, in 2000, the Nobel Prize for Physiology or Medicine. system. In particular, it is of the essence to move from correlation — this neuron or Henry Markram is Professor of Neuroscience at the Ecole Polytechnique Fédérale de Lausanne, brain region is active whenever the subject Switzerland. He researches the principles of neuronal and synaptic organization of the does this or that — to causation — this set neocortex, with the aim of understanding brain diseases. He discovered a series of principles of of molecularly defined neuronal popula- synaptic transmission and plasticity and co‑developed the intense world theory of autism and tions is causally involved in that behaviour. the theory of liquid computing. He has also initiated simulation-based neuroscience as a The power of optogenetics has given us national research programme in Switzerland and the Human Brain Project as a European plan unprecedented power to rapidly, specifically, towards an integrated view of the brain. delicately and reversibly turn specific connections or groups of neurons on and off. Paul M. Matthews is Professor of Clinical Neurosciences and Head of the new Division of Brain Sciences at Imperial College London, UK. He is also Vice President for Integrated Medicines The time is ripe for a concerted project com- Development in the Neurosciences Unit and a Medicine Development Lead at GlaxoSmithKline, bining these precise tools with large high- Brentford, UK. His research interests include molecular and functional neuroimaging and in quality genomic and cellular databases and neurological therapeutics development. Among other activities, he is Chair of the Imaging atlases, multiple physiological observatories Enhancement Working Group for UK Biobank, which intends to phenotype 100,000 people in the to track the spiking activity of large ensem- longitudinal cohort study using advanced imaging of the brain, heart, carotids, bones and body, bles of neurons in behaving animals under and is leading the UK OPTIMISE Consortium for Stratified Medicine in Multiple Sclerosis. Paul M. highly standardized conditions, and anatom- Matthews’ homepage: http://www1.imperial.ac.uk/departmentofmedicine/divisions/ ically and biophysically accurate computer brainsciences/ simulations and theoretical studies. Rafael Yuste is Professor of Biological Sciences and Neuroscience at Columbia University, New York, USA. He obtained his M.D. at the Universidad Autónoma in Madrid, Spain, worked in Sydney What are the challenges facing these Brenner’s laboratory at the MRC Laboratory of Molecular Biology in Cambridge, UK, carried out his projects? Are there lessons to be learned Ph.D. studies with Larry Katz in Torsten Wiesel’s laboratory at Rockefeller University, New York, from other large-scale biology projects (the USA, and was a postdoctoral student of David Tank at AT&T Bell Laboratories, Murray Hill, New Human Genome Project, for example)? Jersey, USA. In 1996, he joined the Department of Biological Sciences at Columbia University. In 2005, he became a Howard Hughes Medical Institute investigator and a co‑director of the Kavli E.R.K. There are enormous challenges facing Institute for Brain Circuits at Columbia University. He has pioneered the application of optical these projects because the human brain is so imaging techniques to study the structure and function of the cortex, and he first proposed, complex. These projects are unlike anything 1,3 together with a group of colleagues, the Brain Activity Map . Rafael Yuste’s homepage: http:// undertaken before. It therefore is essential www.columbia.edu/cu/biology/faculty/yuste/index.html that we first study the terrain to be covered Christof Koch is Chief Scientific Officer at the Allen Institute for Brain Science in Seattle, and begin with more tractable goals — for Washington, USA. He studied physics and philosophy at the University of Tübingen in Germany and example, understanding the logic of the was awarded his Ph.D. in biophysics. In 1986, he joined the California Institute of Technology, worm and the fly brain, and understanding Pasadena, USA, as a Professor of Biology and Engineering, where he remained until 2013. He has sensory, motor and cognitive systems in the authored more than 300 scientific papers, patents and books on the biophysics of nerve cells, and mammalian brain. In parallel, we need to the neuronal and computational bases of visual perception, attention and, together with Francis improve imaging capabilities for the human Crick, of consciousness. Christof Koch’s homepage: http://www.klab.caltech.edu/koch/ brain and to develop more precise meth- odologies for measuring neural activity in humans. What I gather is being planned for how neuroscience can be an exciting area of Rafael Yuste. The BRAIN Initiative will the BRAIN Initiative, which has a superb blue skies discovery research and an engine promote the development of novel tech- advisory committee, is a series of study of economic recovery. We also need them nological platforms for neuroscience. The groups to outline the tasks to undertake and to change the way we do neuroscience. The exact focus is being decided by the three the sequence in which to undertake them. ‘big’ problems of the brain demand inter- funding agencies involved and their panels of As I indicated, there are no precedents disciplinary approaches. There is so much experts and will become clear in a couple for this. The Human Genome Project was in the present system that creates barriers of months. I expect it will focus on technol- important and successfully executed, but it between investigators and institutions and ogies to perform systematic measurements was much simpler. We knew exactly what that slows (or even impedes) free flow of and manipulations of the activity of large the end point was. We needed to obtain the information. We need examples that show numbers of neurons in animal models and whole sequence of nucleotides that makes up how to change this. in human patients. the human genome. Further, we knew how

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to reach this end point. It therefore became code of information and the logical trans- The lessons that I draw are that, if the a challenge of organization and production: formations of that information. Although it BRAIN Initiative and the Human Brain to develop sequencing methods that were might be tempting to push the analogy with Project are to succeed, they need to provide quicker and less expensive. For these large the genetic code and transcription, the logic a clarity of vision and to enunciate well- neuroscience projects, we do not have a of neuroscience will be far more complex defined, achievable goals from the start. genetic code. Indeed, we must discover the and diverse. They also need to maintain coordination and rigour in approach without limiting the H.M. The Human Brain Project is a openness to new directions necessary for Glossary technology-driven project with set mile- discovery science. Allen Institute for Brain Science stones and deliverable outcomes. We have The Allen Institute for Brain Science is an independent promised to develop information computer R.Y. In this difficult funding climate, the non-profit medical research organization. Launched in technology platforms that will give us a BRAIN Initiative can be perceived as a 2003 with a seed contribution from founder and new foundation for studying the brain. The ‘zero-sum game’, in that it will automatically philanthropist Paul G. Allen, it uses a big science approach to generate comprehensive mouse, monkey and Human Brain Project’s platforms will give result in the diminishing of other fund- developing and adult human brain atlas resources. In scientists a single point of access to neuro- ing for current neuroscience projects. This 2012, Allen committed an additional US$300 million for science data, multiomic clinical data and perception is wrong, as it is precisely these the first 4 years of a 10‑year plan to further propel and analysis tools from all over the world. The type of novel proposals that could help expand the institute’s scientific programmes, bringing his platforms will allow them to reconstruct to highlight the importance of neurosci- total commitment to date to $500 million. The Allen Institute’s data and tools are publicly available online. and simulate the brain on supercomputers ence research to the public and lead to an coupled to virtual bodies acting in virtual increase in neuroscience research funding Brain Activity Map environments (in silico behaviour), and overall. For example, the Human Genome The Brain Activity Map project was proposed by an provide them with pipelines to develop Project led to the unexpected development independent group of American researchers sponsored by the Kavli Foundation. The project’s goals — to develop simplified brain models for implementa- of a new industry, with an enormous impact novel tools to measure, manipulate and model the activity tion in neuromorphic computing systems. on the economy. The lesson learned is that of neurons in living brains — came about from a meeting in We are confident that we can deliver what investing in technology development opens 2011 held by private philanthropic organizations (the Kavli we have promised. This does not mean that new areas of economic benefit. Foundation, the Allen Institute for Brain Science and the one automatically understands the brain; Gatsby Charitable Foundation). The project aims to generate a dynamic map of the brain — that is, a ‘functional it means we have a better chance to do so. C.K. The comprehensive brain observa- connectome’ — and to achieve systematic measurements Of course, there are obvious challenges in tory project that we initiated last year will of neural activity in complete neural circuits. This will any big science project: the Human Brain involve several hundred scientists, engineers require the development of novel imaging or nanoelectronic Project will coordinate some 150 research and technicians, and can be thought of as an technologies that can capture the activity of every individual neuron, and will be complemented by techniques groups distributed across 86 institutions in experiment in the sociology of neuroscience to systematically manipulate and computationally analyse 22 countries. But the biggest challenge for with unique organizational challenges. It the activity of these circuits. The Brain Activity Map was our project will be to trigger a phase shift in requires rewarding the team for the collective endorsed by the US government and subsumed by the the way we do neuroscience. Our goal is to effort rather than a few lead investigators. It BRAIN Initiative (Brain Research through Advancing promote a radically new collective, syner- signals the arrival of large-scale science in a Innovative Neurotechnologies Initiative), after the official announcement of the BRAIN Initiative by the US gistic and integrative approach that allows field populated by small groups. By assem- government. neuroscientists to pool the data, knowledge bling a large team of specialists focused on a and expertise that they are generating — common set of goals, techniques and stand- BRAIN Initiative this is the only way we are going to under- ards, MindScope will be able to achieve much (Brain Research through Advancing Innovative Neurotechnologies Initiative). The BRAIN Initiative is a stand the human brain. Another major more than any one scientist can on their own. proposed collaborative research initiative that aims to challenge will be ‘translation’ — working High-energy physics and astrophysics have accelerate the development and application of new with industry to translate research results successfully carried out projects involving technologies that will enable researchers to examine how into new treatments for brain disease and hundreds to thousands of scientists, engineers individual cells and complex neural circuits interact in new technologies. and technologists over several decades, and both time and space. The BRAIN Initiative has been projected to cost more than US$100 million per year for we are learning from their experience. In a 10 years and will be led by the US National Institutes of P.M.M. The BRAIN Initiative and the Human manner comparable to how physical scientists Health (NIH), the Defense Advanced Research Projects Brain Project both face a fundamental chal- build instruments to gaze at distant events at Agency (DARPA), and the National Science Foundation lenge: we do not have a strong paradigm the edge of the universe, brain scientists must (NSF). An advisory group is in the process of developing a scientific plan that will identify areas of high priority and to guide inquiry. It is striking that both the build observatories to peer at proximal events develop some principles for achieving the goals of the BRAIN Initiative and Human Brain Project inside the skull that give rise to the mind that BRAIN Initiative. are ‘big data’ collection exercises from which wonders. meaningful relationships are anticipated to Human Brain Project emerge. By contrast, the Human Genome When will we begin to see the fruits of The Human Brain Project involves over 80 European and international research institutions and aims to bring Project — a success of biology ‘big science’ these endeavours (short-term goals), together existing knowledge about the human brain to with which the BRAIN Initiative has been and what effects are they likely to have on develop supercomputer-based models and simulations. compared — was simply an engineering neuroscience research? Such digital brains may be able to represent the inner project: what needed to be done was precisely workings of a single neurons or even the whole brain. The E.R.K. project is planned to run for 10 years and will be defined and the principles established. It was A serious concerted effort on the coordinated at the Ecole Polytechnique Fédérale de matter of scaling the effort up and making it worm and fly brain could lead to a dramatic Lausanne (EPFL) in Switzerland. affordable. increase in the understanding of the human

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brain in the next decade. I believe that rapid and exploit these principles to fill the large electrophysiological properties of single corti- developments in the parallel fields of neu- gaps in our current data and knowledge. For cal neurons with their dendritic and axonal roscience, molecular biology, immunology instance, we can use principles about the way projection patterns and the genes that they and cell biology (for example, stem cell biol- neurons connect to predict the connectome. express in their cell bodies; third, to describe ogy) could accelerate the impact that the Hypothetical reconstructions of the brain can the functional properties of genetically iden- fundamental discoveries in model systems guide and accelerate experimental mapping tified neurons throughout the ten or more such as worms, flies, mice and monkeys have of the brain, turning it from a dream into a cortical regions of behaving mice; and fourth, on the development of treatments in human practical reality. to generate in silico models of their spiking patients. So while the total impact will require behaviour. As in the past, all of this data will a long-term investment, there are likely to be P.M.M. These projects are at an early stage be freely available via dedicated web tools. important dividends along the way. — the grand vision for the Human Brain The potential impact of these projects Project was only released at the end of 2012, Could you envisage these projects is enormous. The most important would and the BRAIN Initiative is still in a con- sharing information and informing the be to better understand, and therefore be sultation stage. My guess is that it will take direction of each other? able to treat, the devastating diseases of a couple of years to see what form they will the brain that haunt human kind: schizo- take. What I expect from the Human Brain E.R.K. It would be valuable for the American phrenia, depression, bipolar disorder, Project in the short term is an acceleration and the European projects to continuously post-traumatic stress disorder, addiction, of current human brain neuroscience efforts inform and enrich one another for the Alzheimer’s disease, amyotrophic lateral already undertaken in Europe but with a mutual benefit of both and for society at sclerosis, parkinsonism — the list goes on. greater spirit of common purpose and more large. To the extent that the Human Brain In addition, insights from these projects will movement of people between laboratories Project exposes principles of computation, it give us a better understanding of what is and countries. There will be an increase in could provide insights that bear on the inter- unique about the human mind, for example, training and a ‘step change’ in opportunities pretation of the facts about the brain that by shedding light on how we make deci- in theoretical neuroscience. I am more scep- will be furnished by the Brain Activity Map. sions and the nature of consciousness, free tical about the delivery of the novel comput- Of course, the computational efforts of the will and creativity. ing architectures or the in silico human brain Human Brain Project will be both nourished that they propose, even within the decade, and challenged by the data generated by the H.M. The Human Brain Project will start on but I would be delighted to be proved wrong! Brain Activity Map. 1 October 2013. Just 18 months later we plan The BRAIN Initiative may be expected Finally, we may begin to see, in funda- to deliver a first-draft version of our platform to deliver new tools for functional analyses mental terms, the principles underlying the for use by researchers within the Consortium. of circuit activity in animal models, initially organization of the brain, what aspects of In month 30, we will make the platforms within a limited community in 3–4 years and brain functioning are preserved and what is available to the world scientific community. then more widely over 5‑plus years. The sen- unique to higher primates and to humans. Over 10 years, the Human Brain Project will sor systems engineered could be at the core dedicate €200 million to fund independent of a new approach to design brain–machine H.M. Definitely. The Human Brain Project research projects using the Human Brain interfaces. Perhaps we could expect to see is developing both bottom‑up (biologically Project platforms. The platforms will allow practical translation of the latter as real based) and top-down (theory-based) models. scientists from outside the Consortium to devices even within 5–7 years. I hope that Both approaches are data-driven. The more hunt for, organize and analyse neuroscience new principles might emerge from this effort data we have, the more biologically accurate data. It will give them access to clinical data and its spin-offs within the decade. the models will become. From the Human from huge numbers of patients with every Together, these projects could deliver a Brain Project perspective, the data gener- possible brain disease. It will offer them the mechanistic model for elements of cognition ated by the BRAIN Initiative will provide tools and data that they need to develop pre- before 2025. New technologies and exploita- benchmarks for validating the models we dictive algorithms: for instance, to predict tion opportunities will emerge. They will build. Conversely, Human Brain Project neuron morphologies from patterns of gene also foster a new, bigger (and I hope even models will make it possible to perform expression. Researchers will be able to recon- bolder) generation of neuroscientists. in silico experiments that are impossible to struct brain models of the healthy and dis- perform on biological tissue. If the BRAIN eased brain and perform in silico experiments R.Y. There will probably be technologies Initiative project manages to record from all with the models and compare the results with (such as novel optical methods for imaging the neurons in the human brain simultane- those from biological experiments. They large-scale neuronal activity) that could be ously, researchers will eventually need to use will be able to couple brain models to virtual released to the community in 3 years, but it biologically accurate human brain models robots acting in virtual worlds and perform of course depends on the exact focus of the to help understand the machinery that gives in silico behavioural studies. They will also be BRAIN Initiative’s funding. rise to the vast spectrum of spiking pat- able to implement simplified versions of brain terns one should expect to observe. Spiking models in neuromorphic devices that are suit- C.K. We are milestone-driven. Our goals over of neurons is just one out of thousands of able for integration in robots and other kinds the next 3 years are: first, to construct massive dimensions that could be recorded in the of devices. online databases of the meso-scale connectiv- whole brain. The model can hopefully help to Scientifically, we want to open the road ity of genetically identified cell types through- fill in the missing dimensions. We are at the to a new form of accelerated neuroscience out the brain in thousands of mice sampled stage in the history of neuroscience in which in which we identify basic principles span- at the sub‑micrometre level; second, to sys- experiment, theory and simulation will start ning multiple levels of brain organization tematically classify cell types by linking the to merge. Exciting!

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P.M.M. These projects are highly com- of intensifying our research and increase not only to be seen to push the frontiers of plementary. They individually address funding. As world populations age, the knowledge but also to deliver on economic, ‘tools and rules’ in the United States (new burden of brain disease is rising to unsus- social or health needs. These projects have sensors and circuit characterization) tainable levels. We cannot continue with the potential to do this. In general, there is and Europe (new approaches to massive business as usual. no ‘best way’ of conducting research because data integration and mining), respectively. Today, investment in neuroscience ‘research’ does not have only one kind of Linking the American reductionist and research is growing exponentially. This is objective. However, I strongly believe that at European more holistic approaches seems good news. But we are still talking about the basis of all of the best research is an open- like a good strategy. Each should inform research by individual groups and scientists. ness to new ideas, transparency of approach directions for the other. What is missing is a strategy to integrate the and a commitment to the most rapid Importantly, both are committed to open data and knowledge that we are producing. communication. sharing of data, tools and ideas. This is not Without such a strategy, we could gener- the US–Soviet space race! I can only hope ate millions more papers, make many great R.Y. I think that developing novel methods that there will be no barriers between the discoveries and win many more Nobel prizes for monitoring and manipulating the activ- projects. Each needs the other’s success to without ever getting closer to a unified ity of neuronal circuits is the best invest- realize their own. I would urge the leaders to understanding of brain function and the way ment one can make today for the future of actively incentivize cross-fertilization. it breaks down in disease. neuroscience. We are hampered by the general belief R.Y. Yes, I think it will be natural and desir- that we need an Einstein to explain how C.K. The standard, principal investigator- able for this to happen. These large-scale the brain works. What we actually need is driven approach, operating in small labo- projects should aim to coordinate efforts. to set aside our egos and create a new kind ratories on 3‑year grants, has significant of collective neuroscience. Over the next drawbacks. Because students must write C.K. Yes, the Allen Institute for Brain Science 10 years, the Human Brain Project will fund first-author papers to graduate, and fac- collaborates with the Human Brain Project, about 5,000 Ph.D. students. Other large neu- ulty must publish in high-impact and and we are coordinating work at a number roscience projects are moving in the same hyper-competitive journals to obtain of levels. Indeed, we just jointly published a direction. All the signs indicate that this grant support and tenure, the academic paper in Neuron2 on large-scale biophysical new generation of neuroscientists will be far research enterprise encourages maximal modelling of the local field potential. The more ready to work in teams than the cur- independence among experiments and cerebral cortex is the most complex sheet of rent generation. This is our true hope for the groups. Selection bias is rampant, and organized matter in the universe. If we want future — Brain 2.0. many experiments are not reproducible. to understand it, all of us need all the help Neuroscience is a splintered field, with we can get from related efforts. P.M.M. Is big science also best science? These circa 10,000 laboratories worldwide pur- are large projects, with a €1.1 billion invest- suing distinct questions with a dizzying Given the amount of resources and ment for the Human Brain Project over variety of tools in a multiplicity of animal therefore funding that both projects 10 years. The US government has pledged species, behaviours and developmental will require, do they represent the best way to an initial $100 million in spending over the time points. Indeed, when attending the conduct neuroscience research? course of 2014 to the BRAIN Initiative, with annual Society for Neuroscience meeting, a $3 billion spend over 10 years envisioned. I am struck by the speed with which its E.R.K.. If they are to be successful, the mon- I cannot think of major new conceptual 60,000 or more practitioners are heading ies necessary for these huge projects are advances that have come directly from such away from each other in all possible direc- great. But they will only be productive if they big science in the past, although there is tions in a sociological Big Bang. While this come from new sources and not reduce the no question that such efforts have enabled is necessary in the romantic, exploratory modest funds now available for the powerful conceptual advances made by individuals phase of any new science, a more system- existing programmes for individual research or smaller groups, with data or tools arising atic and thorough exploration is called for — which are still, far and away the most use- from them. While this is an unfair com- as our field enters a more mature phase. ful method we have to encourage new inno- parison, recall that it was Peter Higgs — a This orthogonality among groups has pre- vations and new insight. single creative scientist — whose theory vented the emergence of common stand- ‘discovered’ the Higgs boson. The big science ards. To gain a competitive edge (and due H.M. In 2012, the worldwide commu- effort of CERN (European Organization to lack of funding to manage and curate nity of neuroscientists published about for Nuclear Research) was important, but it online repositories of data), hard-gained 100,000 peer-reviewed papers on the brain. tested a hypothesis rather than developing structural or functional information is Meanwhile global investment in neurosci- it. Similarly, the Human Genome Project hoarded and rarely made accessible online. ence research amounts to about US$7 bil- has provided the data for discovery of the Molecular compounds and transgenic ani- lion. The annual cost of the Human Brain genetic architecture of disease. It did not mals are only shared after the initial papers Project will add up to about 1.4% of lead to the individual discoveries themselves. describing them have appeared in print. that figure. The idea that Human Brain Nonetheless, publically high-profile, sus- All of this has made comparison across Project will drain funds from neuroscience tained, big-project funding is an effective way laboratories difficult, replication of specific research is a very narrow one. It has already of championing a discipline. Pulling together experiments almost impossible and has put the human brain on the horizon as a a new level of public and political support for significantly slowed progress. Big brain serious target for research, and it will fur- science demands an exciting vision — and science offers an alternative approach to ther raise awareness of the extreme urgency in these days of austerity, the vision needs address many of these shortcomings.

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Eric R. Kandel is at Columbia University, Department of Rafael Yuste is at the Department of Biological 2. Reimann, M. W. et al. A biophysically detailed model Neuroscience, 1051 Riverside Drive, NYSPI-UNIT 25, Sciences, Columbia University, 906 NWC Building, of neocortical local field potentials predicts the critical role of active membrane currents. Neuron New York, New York 10032, USA. 550 West 120 Street, Box 4822, New York, 79, 375–390 (2013). e-mail: [email protected] New York 10027, USA. 3. Alivisatos, A. P. et al. The Brain Activity Map. Science e-mail: [email protected] 339,1284–1285 (2013). Henry Markram is at l’Ecole Polytechnique Fédérale de Lausanne, Quartier de l’Innovation, Bâtiment J, Christof Koch is at the Allen Institute for Brain Science, Competing interests statement CH‑1015 Lausanne, Switzerland. 551 N 34th Street, Seattle, Washington 98103, USA. The authors declare competing financial interests: see Web version for details. e-mail: [email protected] e-mail: [email protected] doi:10.1038/nrn3578 Paul M. Matthews is at the Division of Brain Sciences, FURTHER INFORMATION Department of Medicine, Imperial College, London, Allen Brain Atlas: http://www.brain-map.org/ E515, Burlington Danes, Hammersmith Hospital, BRAIN Initiative: http://www.nih.gov/science/brain/ 1. Alivisatos, A. P. et al. The brain activity map project Human Brain Project: www.humanbrainproject.eu DuCane Road, London, W12 0NN, UK. and the challenge of functional connectomics. Neuron ALL LINKS ARE ACTIVE IN THE ONLINE PDF e-mail: [email protected] 74, 970–974 (2012).

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