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What are the (long-term) goals of theseprojects? Why is now the right time to

invest in them?

Eric R. Kandel. The long-term goal ofthese highly ambitious projects is to gaina better understanding of the anatomical,molecular and circuit bases for the logicaloperations carried out by the human brain.The Human Brain Project (see Human BrainProject), based in Europe and led by H.M.,aims to understand the human brain bysimulating its functions through the useof supercomputers. The Brain Activity Map,with which I am more familiar, will be basedin the United States and coordinated byFrancis Collins, Director of the US NationalInstitutes of Health (NIH), and StoryLandis and Tom Insel, Directors of the USNational Institute of Neurological Disorders

and Stroke (NINDS) and the US NationalInstitute of Mental Health (NIMH),respectively.

These projects may be early for thehuman brain, but it is a good time toundertake these ambitious tasks in experi-mental animals for two reasons. First, inboth simple invertebrate animals, such asworms and flies, and in vertebrates, wehave begun to understand how the brainprocesses sensory information and howthe brain initiates movements. We havealso gained insight into the neural basis

of learning, memory, emotion and evendecision-making. These findings positionscientists, especially in the Brain ActivityMap project, to be able to begin to tacklethe overall organization of brain structureand function.

Second, in recent years, scientists havedeveloped a range of new technological,molecular and computational tools thatallow for more efficient and accurate record-ing from many nerve cells at the sametime, for mapping of connections betweenneurons in the brain, for correlating struc-ture and neural activity with function andfor manipulating neural activity to test thecausal role of defined neuronal elements inbehaviour.

Henry Markram. The Human Brain Projectis building the foundations that we need to

reconstruct and simulate the human brainand its diseases, and to develop related com-puting technologies. This is terribly urgent.Today, we are failing to translate our rapidlyimproving knowledge of the brain into ben-efits for society. Very soon the cost of braindisease will reach 10% of the worlds grossdomestic product (GDP), yet the develop-ment of new treatments is grinding to ahalt. There is still a massive gap between theneuroscience laboratory and the clinic. Inthe same way, we still do not know how touse our knowledge about the brain to build

new computing technologies. Neuroscienceis like the infant brain it is flooded withdata and theories but lacks the ability tobring them together in a unified view. Wepin our hopes on more and more data with-out realizing that experiments can only giveus a small fraction of what we need. Theattempt to reconstruct the human brain asa computer model can provide a new focusfor neuroscience and for clinical and tech-nological research. It will help us to cleanup conflicting reports and teach us howto apply knowledge from animal studies tounderstanding the human brain. Ultimately,it will allow us to discover the fundamentalprinciples governing brain structure andfunction and to predictively reconstructthe brain from fragments of experimentaldata. Without this kind of understanding,we will continue to struggle to develop newtreatments and brain-inspired computing

technologies.

Paul M. Matthews. The Human BrainProject will engage a consortium of 80 neu-roscience centres across Europe to aggregatebrain functional data on an unprecedentedscale, use data-mining techniques to derivean understanding of the way the humanbrain is constructed and then apply what islearned to revolutionize computing and todevelop new approaches for the diagnosisand treatment of brain disease. This is ahugely ambitious remit. A strength of thisproject is the focus on multilevel integra-tion. However, at this early stage, the projectis more aspirational than scientifically welltargeted. It emphasizes a massive scaling upof activities in many areas of neurosciencerather than exhaustively exploring a specificquestion or innovation challenge.

The BRAIN Initiative (Brain Researchthrough Advancing InnovativeNeurotechnologies Initiative; see BRAINInitiative) is still more of a commitmentthan a reality. The specific goals are notset but will be considered over 2013 by anadvisory committee to the US NIH Director.

However, a vision for the BRAIN Initiative,which focused attention on the challengeof developing tools able to describe activ-ity across every cell in a functional unit tocharacterize emergent properties, was setout in a 2012 Neuron paper1 from a groupled by R.Y. Specific opportunities offered by

voltage-sensitive optogenetic probes, wire-less (nano) electrophysiological sensors andsynthetic biology were highlighted.

Why are these initiatives coming now?Politically, we need them to help real sci-ence funding grow. They both emphasize

VIEWPOINT

Neuroscience thinks big(and collaboratively)

Eric R. Kandel, Henry Markram, Paul M. Matthews, Rafael Yuste andChristof Koch

Abstract | Despite cash-strapped times for research, several ambitious collaborative

neuroscience projects have attracted large amounts of funding and media

attention. In Europe, the Human Brain Project aims to develop a large-scale

computer simulation of the brain, whereas in the United States, the Brain Activity

Map is working towards establishing a functional connectome of the entire brain,

and the Allen Institute for Brain Science has embarked upon a 10-year project to

understand the mouse visual cortex (the MindScope project). US President Barack

Obamas announcement of the BRAIN Initiative (Brain Research through Advancing

Innovative Neurotechnologies Initiative) in April 2013 highlights the political

commitment to neuroscience and is expected to further foster interdisciplinarycollaborations, accelerate the development of new technologies and thus fuel

much needed medical advances. In this Viewpoint article, five prominent

neuroscientists explain the aims of the projects and how they are addressing some

of the questions (and criticisms) that have arisen.

P E R S P E C T I V E S

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2013 Macmillan Publishers Limited. All rights reserved
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how neuroscience can be an exciting area ofblue skies discovery research and an engineof economic recovery. We also need themto change the way we do neuroscience. Thebig problems of the brain demand inter-disciplinary approaches. There is so muchin the present system that creates barriersbetween investigators and institutions andthat slows (or even impedes) free flow ofinformation. We need examples that showhow to change this.

Rafael Yuste. The BRAIN Initiative willpromote the development of novel tech-nological platforms for neuroscience. Theexact focus is being decided by the threefunding agencies involved and their panels ofexperts and will become clear in a coupleof months. I expect it will focus on technol-ogies to perform systematic measurementsand manipulations of the activity of largenumbers of neurons in animal models andin human patients.

The time is ripe now because of thedevelopment of different areas of associatedtechnologies, such as optogenetics, syntheticbiology, nanotechnologies, microelectronicsand computational analysis of large-scaledatasets.

Christof Koch. To understand the cer-ebral cortex, we must bring all availableexperimental, computational and theoreti-cal approaches to focus on a single modelsystem. In particular, it is of the essence tomove from correlation this neuron orbrain region is active whenever the subjectdoes this or that to causation this setof molecularly defined neuronal popula-tions is causally involved in that behaviour.The power of optogenetics has given usunprecedented power to rapidly, specifically,delicately and reversibly turn specific con-nections or groups of neurons on and off.

The time is ripe for a concerted project com-bining these precise tools with large high-quality genomic and cellular databases andatlases, multiple physiological observatoriesto track the spiking activity of large ensem-bles of neurons in behaving animals underhighly standardized conditions, and anatom-ically and biophysically accurate computersimulations and theoretical studies.

What are the challenges facing theseprojects? Are there lessons to be learned

from other large-scale biology projects (theHuman Genome Project, for example)?

E.R.K. There are enormous challenges facingthese projects because the human brain is socomplex. These projects are unlike anythingundertaken before. It therefore is essentialthat we first study the terrain to be coveredand begin with more tractable goals forexample, understanding the logic of theworm and the fly brain, and understandingsensory, motor and cognitive systems in themammalian brain. In parallel, we need toimprove imaging capabilities for the humanbrain and to develop more precise meth-

odologies for measuring neural activity inhumans. What I gather is being planned forthe BRAIN Initiative, which has a superbadvisory committee, is a series of studygroups to outline the tasks to undertake andthe sequence in which to undertake them.

As I indicated, there are no precedentsfor this. The Human Genome Project wasimportant and successfully executed, but itwas much simpler. We knew exactly whatthe end point was. We needed to obtain thewhole sequence of nucleotides that makes upthe human genome. Further, we knew how

The contributors

Eric R. Kandel is University Professor at Columbia University, New York, USA, Fred Kavli Professor

and Director at the Kavli Institute for Brain Science at Columbia University and a senior

investigator at the Howard Hughes Medical Institute. A graduate of Harvard College, Cambridge,

Massachusetts, USA, and New York University School of Medicine, New York, USA, he trained in

neurobiology at the US National Institutes of Health, Bethesda, Maryland, USA, and in psychiatry at

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.

His research has been concerned with the molecular mechanisms of memory storage inAplysia

californica and mice. More recently, he has studied mouse models of memory disorders and mental

illness. Kandels work has been recognized with the Albert Lasker Award, the Heineken Award of

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.

Henry Markram is Professor of Neuroscience at the Ecole Polytechnique Fdrale de Lausanne,

Switzerland. He researches the principles of neuronal and synaptic organization of the

neocortex, with the aim of understanding brain diseases. He discovered a series of principles of

synaptic transmission and plasticity and codeveloped the intense world theory of autism and

the theory of liquid computing. He has also initiated simulationbased neuroscience as a

national research programme in Switzerland and theHuman Brain Projectas a European plan

towards an integrated view of the brain.

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

Development in the Neurosciences Unit and a Medicine Development Lead at GlaxoSmithKline,

Brentford, UK. His research interests include molecular and functional neuroimaging and in

neurological therapeutics development. Among other activities, he is Chair of the Imaging

Enhancement Working Group for UK Biobank, which intends to phenotype 100,000 people in the

longitudinal cohort study using advanced imaging of the brain, heart, carotids, bones and body,

and is leading the UK OPTIMISE Consortium for Stratified Medicine in Multiple Sclerosis. Paul M.

Matthews homepage: http://www1.imperial.ac.uk/departmentofmedicine/divisions/

brainsciences/

Rafael Yuste is Professor of Biological Sciences and Neuroscience at Columbia University, New

York, USA. He obtained his M.D. at the Universidad Autnoma in Madrid, Spain, worked in Sydney

Brenners laboratory at the MRC Laboratory of Molecular Biology in Cambridge, UK, carried out his

Ph.D. studies with Larry Katz in Torsten Wiesels laboratory at Rockefeller University, New York,

USA, and was a postdoctoral student of David Tank at AT&T Bell Laboratories, Murray Hill, NewJersey, 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 codirector of the Kavli

Institute for Brain Circuits at Columbia University. He has pioneered the application of optical

imaging techniques to study the structure and function of the cortex, and he first proposed,

together with a group of colleagues, the Brain Activity Map1,3. Rafael Yustes homepage:http://

www.columbia.edu/cu/biology/faculty/yuste/index.html

Christof Koch is Chief Scientific Officer at the Allen Institute for Brain Science in Seattle,

Washington, USA. He studied physics and philosophy at the University of Tbingen in Germany and

was awarded his Ph.D. in biophysics. In 1986, he joined the California Institute of Technology,

Pasadena, USA, as a Professor of Biology and Engineering, where he remained until 2013. He has

authored more than 300 scientific papers, patents and books on the biophysics of nerve cells, and

the neuronal and computational bases of visual perception, attention and, together with Francis

Crick, of consciousness. Christof Kochs homepage:http://www.klab.caltech.edu/koch/


660 | SEPTEMBER 2013 | VOLUME 14 www.nature.com/reviews/neuro

http://www.humanbrainproject.eu/http://www.humanbrainproject.eu/http://www.humanbrainproject.eu/http://www1.imperial.ac.uk/departmentofmedicine/divisions/brainsciences/http://www1.imperial.ac.uk/departmentofmedicine/divisions/brainsciences/http://www.columbia.edu/cu/biology/faculty/yuste/index.htmlhttp://www.columbia.edu/cu/biology/faculty/yuste/index.htmlhttp://www.klab.caltech.edu/koch/http://www.klab.caltech.edu/koch/http://www.columbia.edu/cu/biology/faculty/yuste/index.htmlhttp://www.columbia.edu/cu/biology/faculty/yuste/index.htmlhttp://www1.imperial.ac.uk/departmentofmedicine/divisions/brainsciences/http://www1.imperial.ac.uk/departmentofmedicine/divisions/brainsciences/http://www.humanbrainproject.eu/


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to reach this end point. It therefore becamea challenge of organization and production:to develop sequencing methods that werequicker and less expensive. For these largeneuroscience projects, we do not have agenetic code. Indeed, we must discover the

code of information and the logical trans-formations of that information. Although itmight be tempting to push the analogy withthe genetic code and transcription, the logicof neuroscience will be far more complexand diverse.

H.M. The Human Brain Project is atechnology-driven project with set mile-stones and deliverable outcomes. We havepromised to develop information computertechnology platforms that will give us anew foundation for studying the brain. TheHuman Brain Projects platforms will givescientists a single point of access to neuro-science data, multiomic clinical data andanalysis tools from all over the world. Theplatforms will allow them to reconstructand simulate the brain on supercomputerscoupled to virtual bodies acting in virtualenvironments (in silico behaviour), and

provide them with pipelines to developsimplified brain models for implementa-tion in neuromorphic computing systems.We are confident that we can deliver whatwe have promised. This does not mean thatone automatically understands the brain;it means we have a better chance to do so.Of course, there are obvious challenges inany big science project: the Human BrainProject will coordinate some 150 researchgroups distributed across 86 institutions in22 countries. But the biggest challenge forour project will be to trigger a phase shift inthe way we do neuroscience. Our goal is topromote a radically new collective, syner-gistic and integrative approach that allowsneuroscientists to pool the data, knowledgeand expertise that they are generating this is the only way we are going to under-stand the human brain. Another majorchallenge will be translation workingwith industry to translate research resultsinto new treatments for brain disease andnew technologies.

P.M.M. The BRAIN Initiative and the HumanBrain Project both face a fundamental chal-

lenge: we do not have a strong paradigmto guide inquiry. It is striking that both theBRAIN Initiative and Human Brain Projectare big data collection exercises from whichmeaningful relationships are anticipated toemerge. By contrast, the Human GenomeProject a success of biology big sciencewith which the BRAIN Initiative has beencompared was simply an engineeringproject: what needed to be done was preciselydefined and the principles established. It wasmatter of scaling the effort up and making itaffordable.

The lessons that I draw are that, if theBRAIN Initiative and the Human BrainProject are to succeed, they need to providea clarity of vision and to enunciate well-defined, achievable goals from the start.They also need to maintain coordinationand rigour in approach without limiting theopenness to new directions necessary fordiscovery science.

R.Y. In this difficult funding climate, theBRAIN Initiative can be perceived as azero-sum game, in that it will automaticallyresult in the diminishing of other fund-ing for current neuroscience projects. Thisperception is wrong, as it is precisely thesetype of novel proposals that could helpto highlight the importance of neurosci-ence research to the public and lead to anincrease in neuroscience research fundingoverall. For example, the Human Genome

Project led to the unexpected developmentof a new industry, with an enormous impacton the economy. The lesson learned is thatinvesting in technology development opensnew areas of economic benefit.

C.K. The comprehensive brain observa-tory project that we initiated last year willinvolve several hundred scientists, engineersand technicians, and can be thought of as anexperiment in the sociology of neurosciencewith unique organizational challenges. Itrequires rewarding the team for the collectiveeffort rather than a few lead investigators. Itsignals the arrival of large-scale science in afield populated by small groups. By assem-bling a large team of specialists focused on acommon set of goals, techniques and stand-ards, MindScope will be able to achieve muchmore than any one scientist can on their own.High-energy physics and astrophysics havesuccessfully carried out projects involvinghundreds to thousands of scientists, engineersand technologists over several decades, andwe are learning from their experience. In amanner comparable to how physical scientistsbuild instruments to gaze at distant events at

the edge of the universe, brain scientists mustbuild observatories to peer at proximal eventsinside the skull that give rise to the mind thatwonders.

When will we begin to see the fruits ofthese endeavours (short-term goals),

and what effects are they likely to have onneuroscience research?

E.R.K. A serious concerted effort on theworm and fly brain could lead to a dramaticincrease in the understanding of the human

Glossary

Allen Institute for Brain Science

The Allen Institute for Brain Science is an independent

non-profit medical research organization. Launched in

2003 with a seed contribution from founder and

philanthropist Paul G. Allen, it uses a big science approach

to generate comprehensive mouse, monkey and

developing and adult human brain atlas resources. In

2012, Allen committed an additional US$300 million for

the first 4 years of a 10-year plan to further propel and

expand the institutes scientific programmes, bringing his

total commitment to date to $500 million. The Allen

Institutes data and tools are publicly available online.

Brain Activity Map

The Brain Activity Map project was proposed by anindependent group of American researchers sponsored by

the Kavli Foundation. The projects goals to develop

novel tools to measure, manipulate and model the activity

of neurons in living brains came about from a meeting in

2011 held by private philanthropic organizations (the Kavli

Foundation, the Allen Institute for Brain Science and the

Gatsby Charitable Foundation). The project aims to

generate a dynamic map of the brain that is, a functional

connectome and to achieve systematic measurements

of neural activity in complete neural circuits. This will

require the development of novel imaging or nanoelectronic

technologies that can capture the activity of every

individual neuron, and will be complemented by techniques

to systematically manipulate and computationally analyse

the activity of these circuits. The Brain Activity Map was

endorsed by the US government and subsumed by the

BRAIN Initiative (Brain Research through Advancing

Innovative Neurotechnologies Initiative), after the official

announcement of the BRAIN Initiative by the US

government.

BRAIN Initiative

(Brain Research through Advancing Innovative

Neurotechnologies Initiative). The BRAIN Initiative is a

proposed collaborative research initiative that aims to

accelerate the development and application of new

technologies that will enable researchers to examine how

individual cells and complex neural circuits interact in

both time and space. The BRAIN Initiative has been

projected to cost more than US$100 million per year for

10 years and will be led by the US National Institutes of

Health (NIH), the Defense Advanced Research Projects

Agency (DARPA), and the National Science Foundation(NSF). An advisory group is in the process of developing a

scientific plan that will identify areas of high priority and

develop some principles for achieving the goals of the

BRAIN Initiative.

Human Brain Project

The Human Brain Project involves over 80 European and

international research institutions and aims to bring

together existing knowledge about the human brain to

develop supercomputer-based models and simulations.

Such digital brains may be able to represent the inner

workings of a single neurons or even the whole brain. The

project is planned to run for 10 years and will be

coordinated at the Ecole Polytechnique Fdrale de

Lausanne (EPFL) in Switzerland.





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brain in the next decade. I believe that rapiddevelopments in the parallel fields of neu-roscience, molecular biology, immunologyand cell biology (for example, stem cell biol-ogy) could accelerate the impact that thefundamental discoveries in model systemssuch as worms, flies, mice and monkeys haveon the development of treatments in humanpatients. So while the total impact will requirea long-term investment, there are likely to beimportant dividends along the way.

The potential impact of these projectsis enormous. The most important wouldbe to better understand, and therefore beable to treat, the devastating diseases ofthe brain that haunt human kind: schizo-phrenia, depression, bipolar disorder,post-traumatic stress disorder, addiction,Alzheimers disease, amyotrophic lateralsclerosis, parkinsonism the list goes on.In addition, insights from these projects will

give us a better understanding of what isunique about the human mind, for example,by shedding light on how we make deci-sions and the nature of consciousness, freewill and creativity.

H.M. The Human Brain Project will start on1 October 2013. Just 18 months later we planto deliver a first-draft version of our platformfor use by researchers within the Consortium.In month 30, we will make the platformsavailable to the world scientific community.Over 10 years, the Human Brain Project willdedicate 200 million to fund independentresearch projects using the Human BrainProject platforms. The platforms will allowscientists from outside the Consortium tohunt for, organize and analyse neurosciencedata. It will give them access to clinical datafrom huge numbers of patients with everypossible brain disease. It will offer them thetools and data that they need to develop pre-dictive algorithms: for instance, to predictneuron morphologies from patterns of geneexpression. Researchers will be able to recon-struct brain models of the healthy and dis-eased brain and perform in silico experiments

with the models and compare the results withthose from biological experiments. Theywill be able to couple brain models to virtualrobots acting in virtual worlds and performin silico behavioural studies. They will also beable to implement simplified versions of brainmodels in neuromorphic devices that are suit-able for integration in robots and other kindsof devices.

Scientifically, we want to open the roadto a new form of accelerated neurosciencein which we identify basic principles span-ning multiple levels of brain organization

and exploit these principles to fill the largegaps in our current data and knowledge. Forinstance, we can use principles about the wayneurons connect to predict the connectome.Hypothetical reconstructions of the brain canguide and accelerate experimental mappingof the brain, turning it from a dream into apractical reality.

P.M.M. These projects are at an early stage the grand vision for the Human BrainProject was only released at the end of 2012,and the BRAIN Initiative is still in a con-sultation stage. My guess is that it will takea couple of years to see what form they willtake. What I expect from the Human BrainProject in the short term is an accelerationof current human brain neuroscience effortsalready undertaken in Europe but with agreater spirit of common purpose and moremovement of people between laboratories

and countries. There will be an increase intraining and a step change in opportunitiesin theoretical neuroscience. I am more scep-tical about the delivery of the novel comput-ing architectures or the in silico human brainthat they propose, even within the decade,but I would be delighted to be proved wrong!

The BRAIN Initiative may be expectedto deliver new tools for functional analysesof circuit activity in animal models, initiallywithin a limited community in 34 years andthen more widely over 5-plus years. The sen-sor systems engineered could be at the coreof a new approach to design brainmachineinterfaces. Perhaps we could expect to seepractical translation of the latter as realdevices even within 57 years. I hope thatnew principles might emerge from this effortand its spin-offs within the decade.

Together, these projects could deliver amechanistic model for elements of cognitionbefore 2025. New technologies and exploita-tion opportunities will emerge. They willalso foster a new, bigger (and I hope evenbolder) generation of neuroscientists.

R.Y. There will probably be technologies

(such as novel optical methods for imaginglarge-scale neuronal activity) that could bereleased to the community in 3 years, but itof course depends on the exact focus of theBRAIN Initiatives funding.

C.K. We are milestone-driven. Our goals overthe next 3 years are: first, to construct massiveonline databases of the meso-scale connectiv-ity of genetically identified cell types through-out the brain in thousands of mice sampledat the sub-micrometre level; second, to sys-tematically classify cell types by linking the

electrophysiological properties of single corti-cal neurons with their dendritic and axonalprojection patterns and the genes that theyexpress in their cell bodies; third, to describethe functional properties of genetically iden-tified neurons throughout the ten or morecortical regions of behaving mice; and fourth,to generate in silico models of their spikingbehaviour. As in the past, all of this data willbe freely available via dedicated web tools.

Could you envisage these projectssharing information and informing the

direction of each other?

E.R.K. It would be valuable for the Americanand the European projects to continuouslyinform and enrich one another for themutual benefit of both and for society atlarge. To the extent that the Human BrainProject exposes principles of computation, it

could provide insights that bear on the inter-pretation of the facts about the brain thatwill be furnished by the Brain Activity Map.Of course, the computational efforts of theHuman Brain Project will be both nourishedand challenged by the data generated by theBrain Activity Map.

Finally, we may begin to see, in funda-mental terms, the principles underlying theorganization of the brain, what aspects ofbrain functioning are preserved and what isunique to higher primates and to humans.

H.M. Definitely. The Human Brain Projectis developing both bottom-up (biologicallybased) and top-down (theory-based) models.Both approaches are data-driven. The moredata we have, the more biologically accuratethe models will become. From the HumanBrain Project perspective, the data gener-ated by the BRAIN Initiative will providebenchmarks for validating the models webuild. Conversely, Human Brain Projectmodels will make it possible to performin silico experiments that are impossible toperform on biological tissue. If the BRAINInitiative project manages to record from all

the neurons in the human brain simultane-ously, researchers will eventually need to usebiologically accurate human brain modelsto help understand the machinery that givesrise to the vast spectrum of spiking pat-terns one should expect to observe. Spikingof neurons is just one out of thousands ofdimensions that could be recorded in thewhole brain. The model can hopefully help tofill in the missing dimensions. We are at thestage in the history of neuroscience in whichexperiment, theory and simulation will startto merge. Exciting!





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P.M.M. These projects are highly com-plementary. They individually addresstools and rules in the United States (newsensors and circuit characterization)and Europe (new approaches to massivedata integration and mining), respectively.Linking the American reductionist andEuropean more holistic approaches seemslike a good strategy. Each should informdirections for the other.

Importantly, both are committed to opensharing of data, tools and ideas. This is notthe USSoviet space race! I can only hopethat there will be no barriers between theprojects. Each needs the others success torealize their own. I would urge the leaders toactively incentivize cross-fertilization.

R.Y. Yes, I think it will be natural and desir-able for this to happen. These large-scaleprojects should aim to coordinate efforts.

C.K. Yes, the Allen Institute for Brain Sciencecollaborates with the Human Brain Project,and we are coordinating work at a numberof levels. Indeed, we just jointly published apaper in Neuron2 on large-scale biophysicalmodelling of the local field potential. Thecerebral cortex is the most complex sheet oforganized matter in the universe. If we wantto understand it, all of us need all the helpwe can get from related efforts.

Given the amount of resources andtherefore funding that both projects

will require, do they represent the best way toconduct neuroscience research?

E.R.K.. If they are to be successful, the mon-ies necessary for these huge projects aregreat. But they will only be productive if theycome from new sources and not reduce themodest funds now available for the powerfulexisting programmes for individual research which are still, far and away the most use-ful method we have to encourage new inno-

vations and new insight.

H.M. In 2012, the worldwide commu-nity of neuroscientists published about100,000 peer-reviewed papers on the brain.Meanwhile global investment in neurosci-ence research amounts to about US$7 bil-lion. The annual cost of the Human BrainProject will add up to about 1.4% ofthat figure. The idea that Human BrainProject will drain funds from neuroscienceresearch is a very narrow one. It has alreadyput the human brain on the horizon as aserious target for research, and it will fur-ther raise awareness of the extreme urgency

of intensifying our research and increasefunding. As world populations age, theburden of brain disease is rising to unsus-tainable levels. We cannot continue withbusiness as usual.

Today, investment in neuroscienceresearch is growing exponentially. This isgood news. But we are still talking aboutresearch by individual groups and scientists.What is missing is a strategy to integrate thedata and knowledge that we are producing.Without such a strategy, we could gener-ate millions more papers, make many greatdiscoveries and win many more Nobel prizeswithout ever getting closer to a unifiedunderstanding of brain function and the wayit breaks down in disease.

We are hampered by the general beliefthat we need an Einstein to explain howthe brain works. What we actually need isto set aside our egos and create a new kind

of collective neuroscience. Over the next10 years, the Human Brain Project will fundabout 5,000 Ph.D. students. Other large neu-roscience projects are moving in the samedirection. All the signs indicate that thisnew generation of neuroscientists will be farmore ready to work in teams than the cur-rent generation. This is our true hope for thefuture Brain 2.0.

P.M.M. Is big science also best science? Theseare large projects, with a 1.1 billion invest-ment for the Human Brain Project over10 years. The US government has pledgedan initial $100 million in spending over thecourse of 2014 to the BRAIN Initiative, witha $3 billion spend over 10 years envisioned.I cannot think of major new conceptualadvances that have come directly from suchbig science in the past, although there isno question that such efforts have enabledconceptual advances made by individualsor smaller groups, with data or tools arisingfrom them. While this is an unfair com-parison, recall that it was Peter Higgs asingle creative scientist whose theorydiscovered the Higgs boson. The big science

effort of CERN (European Organizationfor Nuclear Research) was important, but ittested a hypothesis rather than developingit. Similarly, the Human Genome Projecthas provided the data for discovery of thegenetic architecture of disease. It did notlead to the individual discoveries themselves.Nonetheless, publically high-profile, sus-tained, big-project funding is an effective wayof championing a discipline. Pulling togethera new level of public and political support forscience demands an exciting vision andin these days of austerity, the vision needs

not only to be seen to push the frontiers ofknowledge but also to deliver on economic,social or health needs. These projects havethe potential to do this. In general, there isno best way of conducting research becauseresearch does not have only one kind ofobjective. However, I strongly believe that atthe basis of all of the best research is an open-ness to new ideas, transparency of approachand a commitment to the most rapidcommunication.

R.Y. I think that developing novel methodsfor monitoring and manipulating the activ-ity of neuronal circuits is the best invest-ment one can make today for the future ofneuroscience.

C.K. The standard, principal investigator-driven approach, operating in small labo-ratories on 3-year grants, has significant

drawbacks. Because students must writefirst-author papers to graduate, and fac-ulty must publish in high-impact andhyper-competitive journals to obtaingrant support and tenure, the academicresearch enterprise encourages maximalindependence among experiments andgroups. Selection bias is rampant, andmany experiments are not reproducible.Neuroscience is a splintered field, withcirca 10,000 laboratories worldwide pur-suing distinct questions with a dizzying

variety of tools in a multiplicity of animalspecies, behaviours and developmentaltime points. Indeed, when attending theannual Society for Neuroscience meeting,I am struck by the speed with which its60,000 or more practitioners are headingaway from each other in all possible direc-tions in a sociological Big Bang. While thisis necessary in the romantic, exploratoryphase of any new science, a more system-atic and thorough exploration is called foras our field enters a more mature phase.This orthogonality among groups has pre-

vented the emergence of common stand-ards. To gain a competitive edge (and due

to lack of funding to manage and curateonline repositories of data), hard-gainedstructural or functional information ishoarded and rarely made accessible online.Molecular compounds and transgenic ani-mals are only shared after the initial papersdescribing them have appeared in print.All of this has made comparison acrosslaboratories difficult, replication of specificexperiments almost impossible and hassignificantly slowed progress. Big brainscience offers an alternative approach toaddress many of these shortcomings.





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Eric R. Kandel is at Columbia University, Department of

Neuroscience, 1051 Riverside Drive, NYSPI-UNIT 25,

New York, New York 10032, USA.

e-mail:[email protected]

Henry Markram is at lEcole Polytechnique Fdrale de

Lausanne, Quartier de lInnovation, Btiment J,

CH-1015 Lausanne, Switzerland.


Paul M. Matthews is at the Division of Brain Sciences,

Department of Medicine, Imperial College, London,

E515, Burlington Danes, Hammersmith Hospital,

DuCane Road, London, W12 0NN, UK.


Rafael Yuste is at the Department of Biological

Sciences, Columbia University, 906 NWC Building,

550 West 120 Street, Box 4822, New York,

New York 10027, USA.


Christof Koch is at theAllen Institute for Brain Science,

551 N 34th Street, Seattle, Washington 98103, USA.

e-mail: [email protected]

doi:10.1038/nrn3578

1. Alivisatos, A. P.et al.The brain activity map projectand the challenge of functional connectomics. Neuron74, 970974 (2012).

2. Reimann, M. W. et al. A biophysically detailed modelof neocortical local field potentials predicts the

critical role of active membrane currents. Neuron

79, 375390 (2013).

3. Alivisatos, A. P. et al. The Brain Activity Map. Science339,12841285 (2013).

Competing interests statementThe authors declare competing financial interests: see Web

version for details.

FURTHER INFORMATION

Allen Brain Atlas:http://www.brain-map.org/

BRAIN Initiative: http://www.nih.gov/science/brain/

Human Brain Project: www.humanbrainproject.eu

ALL LINKS ARE ACTIVE IN THE ONLINE PDF


mailto:[email protected]:[email protected]:[email protected]:[email protected]:[email protected]://www.alleninstitute.org/http://www.nature.com/nrn/journal/v14/n9/full/nrn3578.html#affil-authhttp://www.brain-map.org/http://www.brain-map.org/http://www.nih.gov/science/brain/http://www.humanbrainproject.eu/http://www.humanbrainproject.eu/http://www.nih.gov/science/brain/http://www.brain-map.org/http://www.nature.com/nrn/journal/v14/n9/full/nrn3578.html#affil-authhttp://www.alleninstitute.org/mailto:[email protected]:[email protected]:[email protected]

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