Ome sweet ome: what can the genome tell us about the connectome?

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Some neuroscientists argue that detailed maps of synaptic connectivity – wiring diagrams – will be needed if we are to understand how the brain underlies behavior and how brain malfunctions underlie behavioral disorders. Such large-scale circuit reconstruction, which has been called connectomics, may soon be possible, owing to numerous advances in technologies for image acquisition and processing. Yet, the community is divided on the feasibility and value of the enterprise. Remarkably similar objections were voiced when the Human Genome Project, now widely viewed as a success, was first proposed. We revisit that controversy to ask if it holds any lessons for proposals to map the connectome.

Introduction

  • con·nec·to·mics

  • Pronunciation: kə-něk-’tO-miks, kə-něk-’tahm-iks

  • Function: n pl but sing in constr

  • : a branch of biotechnology concerned with applying the techniques of computer-assisted image acquisition and analysis to the structural mapping of sets of neural circuits or to the complete nervous system of selected organisms using high-speed methods, with organizing the results in databases, and with applications of the data (as in neurology or fundamental neuroscience)—compare GENOMICS

see also con nec tome

(From Merriam-Webster Unabridged Dictionary, 2012)

It is possible that some version of this definition will appear in a dictionary at some point. Before that happens, however, the idea of applying an ‘omics-scale’ approach to neural circuit tracing will require considerable vetting. Here, in contrast to common practice in this journal, we take the charge of providing our current opinion seriously. We compare and contrast connectomics with genomics to ask whether mapping neural connections could ultimately have the same kind of value as sequencing genes.

Section snippets

A (very) short history of connectomics

As with almost everything in neuroscience, the idea of mapping circuits can be traced back to Cajal. He enunciated both the neuron doctrine and the law of dynamic polarization [1]. These two ideas, along with Sherrington’s electrophysiological analysis of reflexes, provided the rationale for thinking about brain mechanisms in terms of circuits: Neurons were nodes that were electrically connected to each other via two types of wires, axons and dendrites. The dendrites sent information toward the

The Human Genome Project

The DNA cloning revolution of the 1970s led to a flood of technical innovations for DNA manipulation. These included methods for sequencing DNA (Sanger, Maxam, and Gilbert), automating the sequencing (Hunkapillar and Hood), cloning (Olson) and fractionating (Olson and Cantor) large DNA segments, and PCR (Mullis) [9, 10]. Once the first full sequence of a genome (phage phiX174) had been determined, many scientists began wondering whether these methods could be combined to sequence larger

Objections

The proposal to sequence the human genome was met with skepticism and hostility in many quarters. Contentious issues involved bureaucracy (would the ‘wrong’ agency be chosen to run the program?) and ethics (would the program threaten privacy or access to health care?) as well as scientific merit [9, 11, 13]. Here we focus on just the latter concerns and ask whether similar objections apply to connectomics.

Lessons

Even those who objected to the Genome Project initially are likely to concede its success now. But how did it succeed? Here we consider lessons learned from the Project, including some that could not have been, or at least were not, fully anticipated at the time.

Differences

So far, we have outlined ways in which the history of genomics may help predict the future of connectomics. Given the success of the genome project, these analogies lead to a generally optimistic view. One needs to be cautious in drawing parallels, however, because there are fundamental differences between the two, as well as uncertainties about the latter, which will make mapping the connectome an even more daunting task than mapping the genome.

Conclusions

We envision a time when the idea of studying the brain’s function without knowing how its cells are interconnected will seem as absurd as the idea of studying genetics without knowing genome sequence. Circuit information will be required if we are to understand how differences in brains underlie differences in behaviour—among healthy individuals, in disease, and within single individuals as they mature, write reviews and age. It is premature to predict that a ‘connectome’ of the brain will ever

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

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