Lawrence Berkeley National Laboratory Recent Work

Title A National Network of Neurotechnology Centers for the BRAIN Initiative.

Permalink https://escholarship.org/uc/item/42j6287v

Journal Neuron, 88(3)

ISSN 0896-6273

Authors Alivisatos, A Paul Chun, Miyoung Church, George M et al.

Publication Date 2015-11-01

DOI 10.1016/j.neuron.2015.10.015

Peer reviewed

eScholarship.org Powered by the California Digital Library University of California Neuron NeuroView

A National Network of Neurotechnology Centers for the BRAIN Initiative

A. Paul Alivisatos,1 Miyoung Chun,2 George M. Church,3,7 Ralph J. Greenspan,4 Michael L. Roukes,5,8,* and Rafael Yuste6,9,* 1Kavli Energy NanoSciences Institute, Materials Science Division, Lawrence Berkeley National Lab and Department of Chemistry, University of California, Berkeley, CA 94720, USA 2The Kavli Foundation, Oxnard, CA 93030, USA 3Department of Genetics and Wyss Institute, Harvard Medical School, Boston, MA 02115 USA 4Kavli Institute for Brain and Mind, and Neurobiology Section/Division of Biology, UCSD, La Jolla, CA 92093-0115, USA 5Physics, Applied Physics, & Bioengineering and The Kavli Nanoscience Institute, Caltech, Pasadena, CA USA 92093-0126, USA 6Neurotechnology Center, Departments of Biological Sciences and Neuroscience, Kavli Institute for Brain Science, Columbia University, New York, NY 10027, USA 7Twitter: @geochurch 8Twitter: @attoboy 9Twitter: @yusterafa *Correspondence: [email protected] (M.L.R.), [email protected] (R.Y.) http://dx.doi.org/10.1016/j.neuron.2015.10.015

We propose the creation of a national network of neurotechnology centers to enhance and accelerate the BRAIN Initiative and optimally leverage the effort and creativity of individual laboratories involved in it. As ‘‘brain observatories,’’ these centers could provide the critical interdisciplinary environment both for realizing ambitious and complex technologies and for providing individual investigators with access to them.

Progress in science depends on of physical scientists and engineers to Initiative are yielding significant accom- new techniques, new discoveries, closely unite with neuroscientists in order plishments that can serve as important and new ideas, probably in that to jointly develop new experimental and elements for future neurotechnology, we order. computational tools for neuroscience. believe that achieving the project’s full Our ideas formed the basis of what potentiality—that is, creating large-scale —Sydney Brenner became the BRAIN Initiative (Insel et al., tools—requires efforts anchored within 2013), a national White House Grand the well-validated center paradigm. It is The BRAIN Initiative Today Challenge that currently involves more our view that the technological challenges In our original proposal for a Brain Activity than one hundred U.S. laboratories and that must be surmounted are sufficiently Map (BAM) Project (Alivisatos et al., numerous regional offshoots. The collec- complex that they are beyond the 2012), we emphasized that the scientific tive tackling of this grand challenge in sci- reach of single-investigator efforts; we understanding of the brain has been ence and technology is already widely believe they can only be tackled through hampered by the limitations of traditional perceived to be a national success and highly coordinated, multi-investigator, methods for recording neuronal activity. an example of U.S. leadership in science cross-disciplinary efforts. Below, we These methods largely measure one and technology. Indeed, since its incep- expand on this proposition, outlining our neuron at a time and thus remain ill-suited tion, similar initiatives have been launched reasons and evidence that implementing for probing complex neural circuits that by other countries; this indicates global a network of neurotechnology centers likely operate at higher, emergent levels consensus about the scientific value and can ensure the success of the BRAIN of functionality. To solve the challenges potential of the Initiative. Initiative. of observing and interacting with neural In this NeuroView perspective, we circuitry at these higher levels of revisit an important component of our National Centers Enable Complex, complexity we pointed to the recent ad- original BAM proposal—one that, if real- Transformational Science vances in nanotechnology, molecular re- ized, will significantly leverage the prog- To illustrate the power of the center para- porters, advanced optical and photonic ress achieved by the BRAIN Initiative. digm, we cite three recent and significant systems, and large-scale semiconductor Specifically, we wish to reemphasize the scientific achievements in the biomedical integration. These fields are now suffi- development of a coordinated, national and physical sciences that have been ciently mature to permit their concatena- network of neurotechnology centers, enabled by center-scale efforts. First, we tion into powerful neurotechnologies devoted to the creation and dissemination point to gene-sequencing technology, that will fundamentally transform how of next-generation tools for neuroscience, which has enabled the modern era of ge- neuroscience research is carried out. To neuromedicine, and brain-inspired engi- nomics. Based on previous successes enable this technological coalescence, neering. While the single- or few-investi- with particle accelerators, chromosome we encouraged interdisciplinary teams gator efforts now supported by the BRAIN sorting, and development of computer

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infrastructure, the U.S. Department of such a project is IceCube (Shi et al., ratories to acquire, implement, or Energy first envisioned a national center- 1998), a kilometer-scale neutrino obser- even maintain. Since connectomics based approach for genomics in the vatory at the South Pole that, in 2013, first is an enterprise that requires auto- mid-1980s (Cook-Deegan 1989). It then achieved detection of neutrinos origi- mation and massively parallel data proceeded to fund individual technol- nating outside of our solar system (Aart- acquisition and analysis, it is ogy-oriented laboratories’ efforts to build sen et al., 2015). Its underlying technology sensible for such instruments, or the many initial components essential for was developed, perfected, and assem- even larger future machines, to be developing genome sequencing instru- bled by a highly coordinated network of hosted within one such center to mentation—including improvements to contributing laboratories. These efforts in facilitate research for the entire Sanger sequencing enzymes, fluorescent this network were distributed at various neuroscience community. To this labeling, capillary electrophoresis, etc. points and institutions nationwide but could be added complex future Indeed, it was through subsequent, coor- were coordinated by a National Science instrumentation capable of inte- dinated efforts and partnerships that Foundation-funded center at the Univer- grating connectomics with tran- evolved between two national centers, sity of Wisconsin, Madison. Another scriptomics and cell history, that is, one at Caltech and the other at Applied example is NuStar (Harrison et al., 2013), with developmental lineage and ac- Biosystems, that these individual com- the satellite-based X-ray telescope that tivity (Marblestone et al., 2014). ponents were ultimately concatenated is now beginning to provide astounding Here, candidate technologies may into an integrated technological system new images and insights into black holes also involve specialized super-reso- comprising automated gene sequencing and violent events in the universe’s evolu- lution fluorescent microscopy (Chen instruments, reagents, and software. tion (Perez et al., 2015). NuStar followed a et al., 2015), plus in situ identifica- After evolving through several models, paradigm similar to that of IceCube, in this tion of molecular profiles and the Prism 3700 Sequencer was eventually case through a NASA-funded center led barcodes (Crosetto et al., 2015). upscaled for robust mass production. Its by Caltech astrophysicists. In these, and These complex technologies are, subsequent acquisition by sequencing many other similar examples, the center again, perhaps most appropriate centers worldwide powered the efforts paradigm has harnessed the collaborative for deployment within a center- that culminated in the elucidation of the power of interdisciplinary scientific teams based context. human genome (Springer, 2006). In the to solve critical problems and advance the d Assembly and deployment of ten years following this achievement, frontiers of science. We ask: why should massively multiplexed, implantable the U.S. National Institutes of Health sup- 21st-century neuroscientists continue to electrical or photonic neural nanop- ported an even more aggressive push operate in isolation, when they could robe systems will require large- toward ‘‘next-generation sequencing’’ powerfully organize to tackle major scale semiconductor integration, that ultimately resulted in a million-fold outstanding problems in concert? nanofabrication, robust foundry- improvement in the cost and quality scale production, and big-data of gene sequencing technology. These Scientific Need for National Centers computational resources. If left to breakthroughs resulted in an unantici- for Neurotechnology individual laboratories, these tasks pated economic bonanza: the $3.8 billion We strongly believe that a coordinated cannot be carried out with the level initial federal investment in the Human national network of neurotechnology of reproducibility, robustness, and Genome Project, followed by an addi- centers can play a vital role, both pri- scale of production needed to tional $10.7 billion through 2012, has mary and catalytic, in enhancing neuro- drive next-generation experimental since generated an economic output of science in general, and the progress neuroscience. We believe the tech- $965 billion and more than 4.3 million of the BRAIN Initiative in particular. To nology underlying proof-of-concept job-years of employment (Battelle Tech- support this, we outline four primary subsystems must follow well-vali- nology Partnership Practice for United areas of the BRAIN Initiative that are dated protocols to permit their for Medical Research, 2013). This repre- crucially dependent on significant tech- coordination and transferral to sents an impressive return on investment nology developments—ones that could state-of-the-art industrial foundries, of $65 for every $1 invested. profit critically from a center-based which maintain sophisticated in- In physics and astronomy, the center framework. struments and process tolerances paradigm has long been understood for mass production at a precision to be the means for technologically d Connectomics is the systematic ul- and scale that renders university- ascending what is termed the technology trastructural reconstructions of neu- or national-laboratory-based fabri- readiness level (TRL) index (Moorehouse, ral circuits (Lichtman and Denk, cation obsolete. During their initial 2002). Coordinated, center-scale efforts 2011). Today, some of the most phases of development, the requi- have enabled complex projects to culmi- advanced platforms for large-scale site integration and production of nate in systems that are sufficiently electron microscope-based con- advanced tools for fundamental mature to permit the launching of sophis- nectomics involves the use of in- neuroscience discovery are unlikely ticated experiments and cutting-edge struments with 61 or more beams to be sustained by venture funding exploratory missions with a high probabil- (Lichtman et al., 2014), which are or the commercial sector. We ity of success. A prominent example of far too expensive for individual labo- believe that bringing coherence to

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the process of creating individual computational centers with skilled coordinated, center-based research net- neurotechnology elements, and personnel, supercomputers, and work can provide. then integrating them into complex storage to curate the valuable pub- The sheer diversity of requisite compo- and robust instrumentation sys- lic data sets that will be amassed. nent technologies makes their concate- tems, can only be optimally pursued While some of this could possibly nation impossible without overarching through the center-based para- be carried out by commercial enter- coordination and standardization of ap- digm. prises—as is increasingly done in proaches and interconnections. Centers d Likewise, state-of-the-art optical diverse fields of science—we can provide the galvanizing vision neces- and magnetic resonance imaging believe that access, control, and sary to coordinate the pursuit and technologies require powerful la- analysis of large-scale neurosci- optimization of innovative elements by sers, magnets, and instrumenta- ence databases should, as a the separate laboratory participants. tion that exceeds what individual public resource, remain in the hands Centers are ideal for preserving mission laboratories or universities can typi- of a national center. Here, the coherence and for sustaining the com- cally build, acquire, or maintain Human Genome Project points to a plete ecosystem of elemental operations at cutting-edge performance. For potential path forward, as it has that, by nature, range from the exalted example, progress in optical micro- solved similar data and privacy to the pedestrian. Many of these essen- scopy is limited to the use of challenges. tial operations may not be perceived, commercially available infrared la- in isolation, as sufficiently cutting-edge sers and optics, high-speed modu- Neurotechnology Centers Will to be fundable. Further, many will also lators, large-scale objective lenses, Amplify Single-Investigator be inappropriate for graduate or post- and optical components. This Achievements doctoral researchers; instead, to ensure equipment is not specifically engi- The initial steps of the BRAIN initiative their reliable execution, these activities neered for neuroscience applica- have laid the groundwork for the next crit- could be better carried out by profes- tions. To do so involves specialized ical stages: enabling the development of sional scientists and engineers. Yet it is design knowledge, precision engi- integrated neurotechnology systems generally impossible to sustain skilled neering, and micro- and nanofabri- and, subsequently, the broad dissemina- and experienced technical personnel cation expertise and infrastructure; tion of newly created tools. There could through short-term single-investigator in general, neither individual neuro- be tremendous opportunity for rapid funding. science laboratories nor university progress in the four areas mentioned We also emphasize that neurotechnol- facilities and research institutes are above if the BRAIN Initiative expands ogy development cannot be pursued in equipped for this. This presently beyond its current portfolio of single- an experimental vacuum. At all stages in constrains researchers to the use and few-investigator projects. Efforts of project evolution, the coordinated tech- of existing, commercially available individual laboratories—driven by inde- nological efforts must be directed toward components from the optics or mi- pendent creativity and the exploration of high-profile experimental neuroscience croscopy industries that are de- diverse approaches—will remain critical goals. Hence, they must be co-directed signed for other, more broadly and will be powerfully enabled by this by close partnerships between experi- marketable applications. A similar new network. Rather than drawing away mental neuroscientists, physical scien- case can be made for development resources from individual laboratories, a tists, and engineers. Centers must of magnetic resonance imaging national network of neurotechnology cen- therefore include an inextricable cohort technology; it is primarily driven ters will both anchor and nurture this PI- of experimental neuroscientists—not sim- today by the needs of hospital- scale creativity. In particular, a center- ply as beta adopters, but as integrated based imaging systems, rather based model will enhance the productivity alpha co-developers. The essential tech- than by the research community in and output of individual laboratories: nological development must be driven cognitive neuroscience. removing the essential burden of system- forward by iterative, closed-loop cycles d Finally, advanced storage and atic engineering—an absolutely essential of development, technical validation, computational data mining are inex- yet technical and time-consuming piece neuroscience experiments, and subse- tricable elements that underpin all of the process—thereby permitting indi- quent optimization. emerging neurotechnologies. The vidual labs and scientists to redirect their Finally, in addition to coalescing new in- amount of data collected with the focus and energies toward activities at novations to develop and standardize new neurotechnologies is expected the frontiers: question-posing, problem- next-gen technologies, centers are ideally to dwarf the output of all previous exploration, and concept-inventing. Cen- positioned to enable both technology methodologies (Alivisatos et al., ters will complement this by providing transfer (to enable robust mass produc- 2012). Hence, individual labora- sustained and coordinated technological tion of instrumentation systems) and reg- tories with traditional servers and support to enable greater synergy and ularization of experimental neuroscience cluster-based IT will likely become coherence in long-term planning for protocols (to permit deployment of stan- overwhelmed with an unprece- independent research groups. Realizing dardized, next-generation instrumenta- dented deluge of data without high-TRL neurotechnologies requires the tion platforms to the laboratories of assistance from state-of-the-art disciplined approach that only a highly individual users).

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Toward a National Network of In summary, in celebrating the nascent Adrienne Fairhall and Sebastian Seung for Neurotechnology Centers achievements of the BRAIN Initiative, we thoughtful comments. An earlier version of this manuscript was submitted to the White House’s As a starting point to promote further dis- also aim to amplify and accelerate its Office of Science and Technology Policy in July cussion, we briefly sketch how a network impact. We think it is important that a na- 2015. of neurotechnology centers might be im- tional, public effort be mounted to create plemented and what might constitute a national network of neurotechnology REFERENCES their goals. 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Lett. 81, 5722–5725. and interaction, accelerating, as ‘‘water- We acknowledge support from the ARO and ing holes,’’ progress and ensuring the DARPA (M.L.R., R.Y.), DOE (A.P.A.), Fondation Springer, M. (2006). Am. Lab. 38, 4–8. pour la Recherche et l’Enseignement Superieur, open and effective dissemination of the Paris (M.L.R.), Mathers Foundation (R.J.G., Yuste, R. and Church, G. (2014). Sci. Am. March technology. M.L.R.), NEI (R.Y.), and NHGRI (G.M.C.). We thank 2014, 38–45.

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