The Brain Atlas (Base Pairs Episode 7)

One in six people suffers from a mental disorder, and yet, compared to cancer and infectious disease, neuropsychiatric treatment options have barely improved since the 1950s. But why is that? In this episode of Base Pairs, we explore some of the problems neuropsychiatric drug discovery faces… and how a single, simple method may help.

*Cover image by Vacon Sartirani

~also available on~

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Extras for Episode 7:

The Atlas Expanded

Dr. Tony Zador’s MAPseq method could very well be revolutionary – capable of generating dozens of “maps” of different parts of the brain at a single-neuron resolution. However, Tony will be the first to tell you that his work is only the beginning.

“In general, when new techniques come along, there’s a while where the community sort of figures out what the relative strengths and weaknesses are and then ends up using that new technique in some collection of cases,” Zador explains.

Kebschull & Huang (unpublished), animation by Furth
Kebschull & Huang (unpublished), animation by Furth – Using MAPseq on the mouse brain.

“Certainly there are some weaknesses of our approach,” he added. “The biggest weakness right now is spatial resolution. The advantage of traditional microscopy is that you can actually see the neuron and its fine dendritic processes and the precise trajectory of each one of the axons.”

Seeing individual neurons in action – understanding their trajectory, purpose, and even class – is work that falls more into Dr. Robert Malenka’s realm.

Stanford professor and co-founder of Circuit Therapeutics, Malenka strongly believes in the value of optogenetic drug discovery. It’s an approach that harnesses modern technologies to identify and address broken circuitry on a molecular level – something that can only be achieved through a deep understanding of how each class of neuron should be functioning within a circuit. MAPseq and other connectome projects could help Rob and his colleagues find these troublesome targets.

Circuit Therapeutics. Click here to learn more!
Circuit Therapeutics. Click here to learn more!

One Other Obstacle

In addition to troubles with the pharmaceutical industry itself, Dr. Raymond Hill – former Executive Director, Licensing and External Research, Europe, for the pharmaceutical giant Merck,  suggests there could be another factor holding back neuropsychiatric drug discovery.

Academia, he explains in our interview, may have become so overspecialized that drug discoverers are getting “tunnel vision.”

“I think if you look back to the great empirical scientists of the past – people like Paul Janssen – they were clinicians, they were biologists, they were organic chemists. They seemed to have their finger in many pies,” Hill says. “Although they may not have been true world-class experts in everything they knew about, they were capable of putting all the pieces together and coming up with something that turned out to be a useful drug.”

“Whereas these days we all know more and more about less and less!”

Drs Raymond Hill (L), Robert Malenka, and Anthony Zador (R) (Credit: Imperial College London, Stanford Medicine, Max Gerber)
Drs Raymond Hill (L), Robert Malenka, and Anthony Zador (R) were guests for the Dec 2016 episode of BasePairs.
(Credit: Imperial College London, Stanford Medicine, Max Gerber)

According to Hill, even in an age where a bottomless pool of information is quite literally at the tips of our fingers, it’s easy for scientists to forget there are other sources of data and perspective outside of their own field.

“If I don’t really know what it is I’m looking for and I’m groping around in the dark, then a chat with the chap in the next lab over a cup of coffee may actually give me that inspiration at least to know what to search for on the internet.”

It’s a problem that many scientists have trouble surmounting. However, here at Cold Spring Harbor Laboratory, collaboration is not only encouraged, but celebrated! With its dozens of annual meetings and courses, symposia, and even the first preprint server for the biological sciences, CSHL endeavors to have a quickening impact on promising ideas and projects across the life sciences.

Sharing the Bounty

And what about MAPseq? In the spirit of sharing knowledge, Zador’s lab will continue to share all their results on BioRxiv. What’s more, they hope to provide MAPseq as a service to other labs in the near future.

“In fact, we’re setting up a facility here at Cold Spring Harbor to provide MAPseq as a service to labs that are interested in using it to study whatever connections they’re interested in,” Zador said. “Currently we have a collection of collaborators that we’re working who are applying it to questions like the development of the visual system, the local architecture of the visual system, the architecture of some neural modulatory centers and so forth.”

Want to hear more from Tony? Check out his recent public lecture below!

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