INI Alumni Gregor Schuhknecht and Nuno Da Costa are making headlines

Brain reconstruction is in the news because of the publication of a series of Nature papers by the Machine Intelligence from Cortical Networks (MICrONS) consortium who have described their reconstruction of a cubic mm of mouse visual cortex at sub-micron resolution.  One of the scientists at the heart of the structural work is an INI alumnus: Nuno da Costa. Nuno did his PhD research on cat visual cortex at INI and then stayed on for a postdoc., eventually becoming a Junior Group Leader before being head-hunted by the Allen Institute for Brain Science in Seattle. He co-leads the Network Anatomy Group, who produced and imaged the 28000 serial EM sections needed for the reconstruction, which generated 1.6 petabytes of annotated data. What he and his team have produced is a landmark in the analysis of cortical circuits.

For anyone who has attempted serial-section electron microscopy (EM), this was a highwire act of exceptional virtuosity, pushing to the limits and developing new technologies - and requiring Nuno and his team’s unique combination of skills, tenacity, and the requiring ability to stay awake during the long nights to ensure the ultramicrotome cutting the sections was doing its job (the ultramicrotome sectioning took 12 days, involving two epochs of 5 + 7 days).

Nuno first learned correlated light-and electron microscopy at INI where he also did a lot of optical imaging and single-unit recordings from cat cortex in vivo. He was certainly the one of the most multi-skilled experimentalists to graduate from INI. When he transferred to the Allen in 2013 he down-sized from cat to mouse – mouse cortex having the advantage of being more compact: the cubic mm his team imaged contained 84 000 neurons and their synaptic connections.

Nuno is not the only INI alumnus involved in the MICrONS Consortium, however. Casey Schneider-Mizell, the first author of the paper on inhibitory circuitry published in the Nature series, is also an INI alumnus. It was at INI that Casey was introduced to the analysis of EM images and imbibed the INI spirit of collaboration. Leila Ellabaddy, another first author on one of the Nature papers, is another INI alumnus, as is co-author Adrian Wanner. We should note in passing is that Clay Reid, one of the leaders of the MICrONS Consortium, spent a sabbatical summer in Rodney and Kevan’s lab in Oxford, where he was immersed in the ongoing structure-function experiments, tripping over John Anderson, whose reconstruction business was located in the passage to the lab.

A lively News & Views article on the MICrONS papers appeared in Nature, co-authored by INI alumnus, Gregor Schuknecht. Gregor’s own research also forms a key part of the story, because for his PhD he was able to establish that there is a linear correlation between the size of a synapse in mouse cortex and its strength, so adding a key functional component to help interpret the structure. This collaborative study from INI was also published in Nature and has been widely cited since. At that time INI had the group of highly experienced researchers and the infrastructure needed for what was recognized as an experimental ‘tour-de-force’. Sadly, it would not be possible in INI today.

INI’s contribution to the field that is now known as ‘connectomics’ did not begin with its diaspora of distinguished alumni; its history stretches back to the 1980s when Rodney Douglas and Kevan Martin began their project to describe the structure, function and modeling of the cortical circuitry by combining experimental work with computer simulations. One early success was their 1989 publication with David Whitteridge of, ‘A canonical circuit for neocortex’, which emphasised the recurrent nature of the cortical circuits. This was a very radical departure from the serial feedforward circuits that for decades were the dominant ‘textbook’ model.

This research program drove their development of several tools for the serial reconstruction of identified cortical neurons, including TRAKA, for 3-D light microscope reconstructions, and TrakEM, for 3-D electron microscope reconstructions. The development of TRAKA using early desk-top computers with very limited memory was supported by Mike Fischer of Research Machines, who also supported the ‘Silicon Cortex’ initiative led by Rodney and Misha Mahowald that Adrian Whately was involved in and brought Adrian and Misha as founding INI members. Indeed, this novel cross-disciplinary research program in the Oxford lab. was what attracted the Swiss godfathers of INI to invite Rodney and Kevan to found INI.

The library of TRAKA reconstructions by John Anderson, who spent thousands of hours at the light microscope, formed the database for Tom Binzegger’s epic quantitative synaptic description of the average cortical circuitry in 2004. TrakEM was further developed to TrakEM2 by Rodney and Albert Cardona, who joined INI as a Junior Group Leader. Albert was beginning a dense EM reconstruction of the first instar larva of Drosophila where the challenge was to automate the reconstruction process of 1000s of serial EM sections. John Anderson, Rita Bopp, and German Köstinger all used the INI-house software for their reconstructions of cat and monkey cortical circuits at synaptic resolution.

With all these parallel interests, INI was a lively training ground for future connectomicians. Among them, Julia Buhmann, Nils Eckstein and Jan Funke have continued the path of computer-aided reconstruction they began as students at INI (supervised by Matthew Cook). Nils and Jan are members of the FlyWire Consortium, which has just published the connectome of adult Drosophila. A number of today’s generation of leaders in the field have passed through INI: Sebastian Seung, another senior member of the MICrONSs, made a sabbatical at INI and was awakened to the potential of apply machine learning methods to connectomics, Albert Cardona and Jorgen Kornfeld (both now at Cambridge University) and Adrian Wanner (now at PSI and also a co-author on the MICrONS papers), all lead connectomics initiatives.

INI clearly has a remarkable track record in terms of people they trained and the methods it pioneered and the concepts it originated, and only now we are starting to put this type of data to service of the ideas generated at INI – and there is much more to come.