Our brains are quite complicated. Well, not just our brains, brains in general tend to be complex blobs. What do you want, when each neuron is connected to many, many others? It’s this whole of neuron connections that is referred to as the connectome. (Some might say, and I tend to tentatively agree, that we are our connectomes, see great TED video by Sebastian Seung.)
Anyway, whether we are or aren’t, it’s certain that mapping the neural circuits in our (and other) brains will be a great step forward in neuroscience. But, as you can imagine, mapping the entire connectome is far from easy. A recent article in PLOS Biology suggests a new approach based on DNA sequencing.
In order to convert brain connectivity into a DNA sequencing issue, the authors propose the ‘barcoding of individual neuronal connections’ (aka BOINC), a method that consists out of three steps:
- Each neuron gets a unique sequence of nucleotides, or a DNA barcode. Even through the use of just 20 nucelotides (or DNA letters) an enormous amount of codes can be generated (1012, a rough estimate for the amount of neurons in a human brain is 1011).
- Then, the barcodes of connected neurons must be brought together. Enter the pseudorabies virus, which is known to carry genetic material across synapses, or places where neurons connect with each other.
- Finally, all the barcodes within a neuron (its own plus those of connected neurons) must be pasted together. Here the enzyme phiC31 comes in, which joins the barcodes in pairs. So, each neuron would have as many barcode pairs as it has connections to its colleagues.
Three steps of BOINC.
(Source: Zador et al., 2012)
After these three steps, brain tissue is processed and the DNA sequenced. And hoppa, we have a connectome.
Of course, there is still a lot of work before it’ll go that easily and quickly, as the authors recognize. One of these, is the toxicity of the virus. Another one is that the method needs some extra development if we want to get information on the brain region and cell type, which could be very useful. Further, false positives (connections that don’t exist) and false negatives (missing existing connections) are possible. So, some fine-tuning required.
But, there are definitely advantages as well. Local and long-range connections are treated equal, you get ‘direct access’ to the neuron and, importantly, it markedly decreases time and costs as the time and cost of DNA sequencing are dropping prodigiously. An estimate provided by the authors concerning the connectome map of a complete mouse cortex turns out to be $48 000 and one week of work, at the current state of technology. Knowing that DNA sequencing is a technology in a state of rapid development, this could drop significnantly in the coming years.
The final word is for the authors:
Low-cost sequencing of brain circuits could be used as a screening test to generate hypotheses about how circuits change with development, learning, genetic manipulations, or any other experimental factor…
What will we learn from sequencing the connectome? Perhaps it is instructive to turn to the lessons learned from sequencing the human genome. Knowledge of the complete genome provides the starting point for much of modern biological research, transforming how research is conducted in the post-genomic era. A cheap and rapid method for deciphering the wiring diagram of an entire brain may have a comparably profound impact on neuroscience research.
For a more elaborate and eloquent exposition of this research, check out this post on the Scientific American blog Brainwaves. (Or check the free article, reference below).
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Zador, A.M., Dubnau, J., Oyibo, H.K., Zhan, H., Cao, G., & Peikon, I.D. (2012). Sequencing the Connectome PLOS Biology, 10 (10) DOI: 10.1371/journal.pbio.1001411
