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by Gabriel Filsinger
figures by Bradley Wierbowski

Brain diseases and age-related neurological disorders are a growing strain on society, and their impact is poised to expand alongside the aging world population. Due to protracted effects and the limited availability of cures, the societal cost of these diseases is severe: for example, it has been estimated that 35% of all disease burden in Europe is attributable to brain disorders. The ability to understand or influence neural activity in the brain has the potential to both reduce this disease burden and increase our understanding of thought, behavior, and consciousness. Inspired by these multifaceted benefits of brain research, many countries have established large-scale national initiatives to address the need for an improved understanding of the brain.

Despite criticism that large science initiatives detract from the more innovative work that occurs in independent labs, there are definite advantages to conducting collective, planned and coordinated scientific endeavors at the national or international scale. Bringing together a large number of scientists and engineers, directing them toward a specific task, and providing significant monetary support allows scientists to accomplish things that wouldn’t be possible in solitude. The Apollo moon project is one of the most highly referenced examples of Big Science, and it is very likely that no individual research group would have had the manpower or resources to put a man on the moon alone.

The key feature of collaborative science endeavors is the unification of scientific effort around a specific objective; this makes the choice of objective critically important. If the goal of a national initiative is precise and concrete, such as sequencing the human genome or sending a man to the moon, this clarity can make the initiative more likely to reach its desired outcomes. However, these firm delineations can also be perceived as restricting if the proposed goal is not widely supported by the scientific community; this was the case with the early stages of the Human Brain Project, where researchers objected to the feasibility of building a simulation of the human brain.

Because these collaborative initiatives are supported by billions of dollars, they must be structured appropriately to optimize time and resources. The U.S.-led BRAIN initiative broadly aims to improve our understanding of the brain, with the specific objective of catalyzing the development of innovative neurotechnologies. The dual focus on studying the brain and on developing tools to aid future brain research ideally positions this effort to lead to significant scientific breakthroughs.

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Why now?

Over the past decade there has been a radical improvement in neurotechnology: existing tools allow scientists to ask precise questions about the function of specific neural circuits in the brain and how the activity of those circuits influences behavior. So far, the results are the most striking in model systems. In mice, scientists have been able to activate or suppress specific memories (such as fear) and alter behavior by using light to stimulate relevant cells, and in flies, they have been able to map neural circuits for specific movements and other actions. Additionally, neuroscientists have already begun using single cell sequencing methods to understand the diversity of brain cells in every organism. These recent advances have exponentially increased the number of tools at our disposal to study the brain, and encouraging scientists to work together through the BRAIN initiative will find both new uses for these existing techniques and additional methods for answering neuroscience-related questions.

Goals and milestones for the BRAIN initiative

To achieve a new level of understanding of the mind, neuroscientists need to improve and expand current technologies. Although it is possible to map the connections between small numbers of neurons and use course grained techniques get a general picture of brain activity, it is still very challenging to precisely link neural circuits that span across the brain with cell-level resolution. There is also a need to enhance the cost efficiency and ease of use of tools, understand the function of diverse cell types that make up the brain, and limit the invasiveness of neural recording and stimulation technologies. The BRAIN initiative is designed to address these challenges, as well as provide a framework for other important research including building conceptual and mathematical tools to understand the brain’s activity and apply developing research towards human disease.

Although the BRAIN initiative was announced in April 2013, a detailed plan for its goals and milestones was not released until June 2014. This was intentional: the project leaders wanted to work heavily with the scientific community to set up the initiative’s long term goals and milestones. From early to late 2013, a working group of neuroscience experts convened to review the field and define broad directions for the effort. This working group hosted public workshops and invited additional experts from a wide range of fields to discuss available technologies and future technology developments that would aid the study of the brain. In September 2013, the working group presented its conclusions on high priority areas for research in the form of an interim report to the NIH. After the approval of this report, the working group then met with public and private partners to receive additional feedback. The June 2014 report provided specific details of research objectives, milestones and goals for the next decade of research for the BRAIN initiative.

The BRAIN Initiative is funding 7 major areas of research, all of which are related to tool-development. These areas include: developing technology to identify the diversity of cells that exist in the brain and determine their roles in health and disease; generate circuit diagrams that vary in resolution from synapses of neurons to the whole brain; produce a dynamic picture of the functioning brain by large scale monitoring of neural activity; link brain activity to behavior by interventions that change neural circuit dynamics; analyze data and build new conceptual foundations to understand mental processes; and study the human brain and treat its disorders. An additional area of research aims to use the new technological and conceptual approaches in goals 1-6 to build a comprehensive and integrated understanding of the brain.

The BRAIN initiative’s funding is split into two 5-year periods. Although these research priorities are highly dependent on one another, the first funding period, with an investment of $400 million a year, will focus on developing technology and methods to study the mind from 2016-2020, while the second funding period, with an investment of $500 million a year, will focus on applying these tools to build a conceptual understanding of the brain between 2021 and 2025. The total research objectives of the BRAIN initiative are actually broader than this core effort, as the official initiative includes partner organizations like DARPA (Defense Advanced Research Projects Agency) and IARPA (Intelligence Advanced Research Projects Activity) who each bring their own funding but have additional goals.

Lessons from other large-scale science initiatives

There are two lessons from past collective science endeavors that support the current organization and priorities of the BRAIN initiative.

  1. It is important to have large, feasible scientific goals with smaller, intermediate goals, but lack of prior understanding should not impede future innovation.

Two previous large-scale science initiatives, the War on Cancer and the Human Brain Project, were both initially criticized by the scientific community because they promised goals that seemed unreachable. Dr. Benjamin Neel, head of the Ontario Cancer Institute, said “promising to find a cure for cancer during the 1970’s (the goal for the War on Cancer) was like promising to reach the moon in the 1600’s”.  Although some of the BRAIN initiative’s objectives also seem fantastic, experts in the field built the milestones through a collective planning process, coming to a consensus on goals for the project. The spectrum of planned research objectives span from risky, but potentially revolutionary, tools to important, but more attainable, applications of current methods that are likely achievable given the state of the field. Although it may not be possible to fully understand the brain, the proposed development of tools will certainly improve our current knowledge.

  1. The development of tools that are significantly easier to use, cheaper, or more efficient than before can produce the biggest impacts on society.

The Human Genome Project is one of the major recent examples of a national biology initiative. It was amazingly successful, with every dollar invested eventually contributing $141 to the economy. A detailed analysis of the initiative reveals that some of the biggest impacts came from the technology development phase, which focused on the development of next-generation sequencing technology. Using only 6% of the project’s overall expenditures, this effort dropped the cost of sequencing a million fold in six years. This cost reduction allowed genome sequencing to move from an expensive, one-time event to a routine process. Although sequencing the first human genome was important, the real impact of this project (and the source of economic growth) arguably came from the ability to sequence genomes thousands of times, in a variety of contexts and genetic backgrounds, and across a variety of different organisms. Democratizing the process of genome sequencing allowed people to use the new technology for a host of new applications. The BRAIN initiative’s priority for tool development, which will make it easier to record or stimulate precise regions of neurons across the brain, will improve the chances that it has a similar impact on society.

It is the ideal time in science to make a sustained national effort to unlock the secrets of the brain, not because the effort is more important now than before, but because of how close the field is to making important discoveries. Navigating these coming revolutions in an organized manner will make further progress as efficient and impactful as possible.

Gabriel Filsinger is a 2nd year PhD Candidate in the Systems Biology program at Harvard Medical School studying genome engineering and synthetic biology.

This article is part of the April 2016 Special Edition on Neurotechnology.

Further Reading:

To learn more about the BRAIN Initiative, you can browse the July 2014 working group report here.

To read more about the backdrop and pitfalls for large science initiatives you can look at a story about the initial struggles of the European brain initiative, the Human Brain Project here.

To read one professor’s takeaways from the Human Genome Project, a previous U.S. science initiative, you can read about George Church’s 4 lessons here.

Cover image from the NIH Image Gallery.

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