Sydney Brenner and the case of the broader world

The incidental journalist

By Albert Cardona, April 19th, 2020.

Sydney Brenner was a scientist extraordinaire whose impact is beyond measure. My naive self, back in 2012 or so, just barely aware of who he was and what he had done, run into his train of thought like a fly onto a wall.

In the early days, the HHMI Janelia research institute (which opened in 2006) awarded Sydney--and several others--a Senior Fellow position, endowed with a small budget for visiting and conducting research among the resident labs. As a visiting scientist (2008--2011), I jump-started my research career by, towards the end of my postdoc at the Hartenstein lab [1], setting up an open source automatic imaging software (Leginon) for serial section electron microscopy (Cardona et al. 2010) in the newly established electron microscopy facility at Janelia. Running into Sydney having lunch at the cafeteria [2] was a rare and very sought-after treat.

Soon after my recruitment as a lab head late in 2011 [3], I asked him--over an informal lunch--why did they choose to reconstruct the connectome of the worm from 5 overlapping electron microscopy volumes from 5 different individuals. There were many objections to make, but I shut up, because, mind you, I had only merely skimmed, not actually read, the 446-page article (rather, encyclopaedia?) that goes by "The mind of the worm" in the folklore (White et al. 1986, "The structure of the nervous system of the nematode Caenorhabditis elegans"). So why 5 worms?

Sydney had an answer: they predictably and expectedly screwed up--a series of thousands of 50-nanometer serial sections is fragile and hard to deliver complete, and the worm is millimeters long--, but turns out that failure was an integral part of his plans. Because the multiple worms to be used where isogenic: as genetically identical as they could be. (Well, 4 were hermaphrodites, with the other one being a male.). The multiple, isogenic animals imaged in overlapping volumes served another, less known purpose of his connectome research project: to undermine racism.

Recall that Sydney was South African. Growing up in the many horrors and conceptual contradictions of the apartheid, Sydney found an opportunity in his research to stab back at the racists with facts. The prevailing thought back then and there was one of genetic determinism, whereby those with the "right" genes had a "higher" intelligence [4]. Sydney's opinion, paraphrasing, was: "hogwash".

In the nematode C. elegans, Sydney found an organism with a strongly stereotyped and deterministic embryonic development [5]. So he reasoned, if genetic determinism was true, two individuals with identical genomes would have identical wiring diagrams for their nervous systems. Sydney knew that, in C. elegans, two isogenic individuals present the same number of neurons. The key question was whether the numbers and spatial positions of their synaptic contacts were both quantitatively and qualitatively identical, which would imply identical wiring diagrams--and he found that they are not, thanks to the comparative connectomics work done on the overlapping volumes of multiple isogenic worms [6].

Worms with the same genes have different brains--different minds, different behaviors at some level. If a small and cell-deterministic animal like C. elegans can't manage to fully specify its nervous system within its genome, there's no hope whatsoever for other, much larger animals. And therefore, Sydney concluded, at a fundamental level, the precise microcircuitry of a brain isn't specified by the genome down to the last synapse, but merely as gross guidelines and strongly subject to environmental influence [7]. The bigots who pressuposed that genes absolutely determine intellectual ability were full of it, as he had always suspected, and now he had a pile of scientific facts to throw at them. Now that's what I call impact.


Notes

  1. My deep appreciation to my postdoc (and partly PhD) advisor, Hartenstein lab, for giving me enormous freedom. He was happy--for all I know--as long as I was busy doing interesting research and discussing it with him, often in long strolls across the Santa Monica mountains in Los Angeles. A role model to follow. Unsurprisingly, he's been bestowed with lecturing and mentoring awards.
  2. The opening hours of the Janelia cafeteria were carefully restricted (from noon to 1 PM; later opening from 11:30 AM to 1 PM as the institute grew). This had the effect, given the prized isolation of the campus, of increasing the chances of interesting conversations at lunch with other scientists at Janelia, which I credit as the origin of several of my past and current research projects.
  3. Syndey often participated of the lab head recruitment INTErview panels, and he was in mine. When I was asked to defend my research proposal and I said that neuroscience research in an organism whose complete synaptic wiring diagram, or connectome, I could yield soon (that of the larval Drosophila), and in combination with the ability to monitor its behavior and optogenetically manipulate and monitor its neurons, we'd have a clear way forward to make progress in understanding the neural circuit basis of behavior, he approved--his endorsement of my research vision may just as well have been the tipping point. Forever thankful that I was given the opportunity to present my proposal, and grateful that I found the words to make it understandable to others who were then able to see its value. The results, you reader can be the judge today.
  4. Never mind that intelligence isn't trivial to measure. IQ tests don't quite measure intelligence but knowledge and familiarity with a particular cultural environment. And tasks that animals peform automatically are devilishly hard to implement in robotics, such as walking or balacing, and hand reaching. Back then, yet also now, wishful thinking and make-believe approaches to politics, justified by cherry picking scientific findings and generalizing them beyond their domain of application was and remains rampant.
  5. C. elegans's famous embryonic development presents an almost entirely stereotypical sequence of cell divisions, from the zygote to the 959 cells of the adult hermaphrodite (see the Worm Atlas at point 3.2.6 Adult).
  6. A spectacular follow-up work is forthcomming, by the hand of Daniel Witvliet from Mei Zhen's lab, in collaboration with many others, where they analyze full, complete connectomes of (at the last count) 9 different individual C. elegans, including various life stages of the worm.
  7. What today is known as the nature vs. nurture false debate. False, because both are necessary and neither is sufficient. Best explained by Kevin Mitchell in his book "Innate".