Uncle Syd and His Worms

[En español]

Anybody, who does biological research using a model organism, especially those using an invertebrate, has quite invariably come across a certain prevalent hotchpotch of disbelief, cynicism and a reasonably uncomfortable amount of derision in the minds of their peers about the tiny creatures that they use to study biology. 

“So, these flies really have brains?” 

“What do you mean that they sleep?” 

Even today, after several decades of fundamental biological research using fruit-flies and worms, this is still a palpable struggle.

We probably can’t quite imagine how radical the idea seemed when Sydney Brenner thought of establishing a nematode, a soil-dwelling 1mm-long round-worm as a system to ask probably some of the most fundamental questions of genetics and molecular biology. Brenner, who died in Singapore last month, also pioneered in putting molecular biology onto the map as a promising avenue for investigating the fundamentals of biology. 

A model animal to a biologist is almost like a computer to a programmer. They are not really interested in studying the model animal per se but more inclined to ask rather fundamental questions availing the genetics, physiology and behavioral tool-boxes that the model offers. Drosophila, the fruit-fly, was already being studied when Brenner embarked upon his voyage with the worms. For him, Drosophila was too complicated. He didn’t want to go down to bacteria either and the worms provided a reasonable balance. These worms, known as C. elegans according to the scientific nomenclature, live only around for three days, could be grown inexpensively and, being transparent, could reveal rather beautiful anatomical details under a microscope. His adventure to ‘tame a metazoan’, starting around the end of the 1960s, reached a very satisfyingly crucial point in 1998 when C. elegans was celebrated as the first multicellular organism to have its entire genome sequenced. Undoubtedly, this provided an important advance towards the Human Genome Project which followed. His adventure led countless laboratories around the world in delving into using these worms, setting up new labs and projects straddling across decades until this very day; supporting many fundamental questions to be addressed in genetics and physiology and gradually in neuroscience – “I think my real skills are in getting things started…In fact, that’s what I enjoy most, the opening game. And I’m afraid that once it gets past that point, I get rather bored and want to do other things…. I’ve always found it interesting to bring projects to the stage that other people can take them over and develop all the little tricks.”Brenner writes in his autobiography.

His resolute excitement with these worms, even at the very early stages, was quite visionary. In reply to E. C. Dougherty at the University of California, Berkeley who had just sent him a batch of worms in 1963, he wrote, “It is an astounding organism”. Interested in how both developmental schemes and nervous systems are organized in an animal, he was excited to have found a model which would let him rummage into these questions with relative ease and flexibility. Indeed, Brenner, with Nicol Thompson and John White, produced a computer-reconstructed complete wiring diagram of the nervous system of these worms. Brenner (with John Sulston and Robert Horvitz) also traced the lineage of each and every cell in these worms. Finally, the complete worm genome was also sequenced. These three accomplishments, which might have taken just three chronologically arranged sentences to describe, not only had an enormous impact on the study of neurons, cells and genomes, but also fairly revolutionized the way one might choose to look at biological problems. In 2002, Brenner, along with Horvitz and Sulston, received a Nobel prize in physiology. 

In Sydney Brenner’s academic life, the starting focus was not the worms though. He rather gradually moved to the worms to probe basic molecular principles at the organismal level. His primary interest in molecular biology was deeply shaped by the DNA double helix structure, the model of which he went to observe right after it was announced to the world. This trip to Cambridge was a phenomenal experience for him as he recalls, “The double helix was a revelatory experience; for me everything fell into place, and my future scientific life was decided there and then”. The Crick and Brenner duo were then to embark upon a journey that deciphered several mysteries in molecular biology; together or independently, all primarily catalyzed by the double helix. One among these endeavors was the genetic code. Triplets of nucleotide bases in the DNA were thought to be the units (Brenner called them ‘codons’ which is what they are still called today) of reading genetic messages. It was not clear though how one should read them, where to start and whether the codons overlap in the reading frame. Brenner provided a theoretical understanding that the genetic code is non-overlapping as the overlapping codes would introduce limitations to the variety of amino acids (the building blocks of proteins) that these triplets are essentially meant to code for. 

The discovery of messenger RNA, the functional bridge between DNA and amino acids, is arguably Brenner’s most significant discovery. DNA contains the genetic code, and a ribosome makes the protein. DNA resides in an intracellular structure called the nucleus, which is separated from the cytoplasm where the ribosome resides. What functionally connects the DNA in the nucleus to the ribosome in the cytoplasm was an enigma. How does the genetic code travel to the protein factory of the ribosomes? Brenner’s discovery showed that the messenger RNA is involved in this particular task. His biographer, Errol C Friedberg writes, “On more than one occasion, in fact, he has claimed that he is delighted to have been awarded two Nobel Prizes — the first he never received!”

Brenner read ‘The Science of Life’, by H.G. Wells, Julian Huxley and G.P. Wells during his formative years in Science and as he mentioned several times, had a great impact on him. Later, He chose an uncannily similar title for his autobiography: ‘My Life in Science’, published in 2001. His other writing adventure was a series of regular columns (Loose Ends, later to be called as False Starts) in Current Biology between 1994 to 2000. Peter Newmark, editor of Current Biology, writes, “At the time, it seemed outrageous that anyone as busy as Sydney Brenner should be willing to submit to the rigor of writing a personal column to a monthly deadline”. He adds, “We were all wrong. Once Sydney started, he was on a roll…My job was, as Sydney puts it, that of “removing cumbersome phrases and watching for any words that might invoke suits of libel and defamation”. 

He had no evident compulsion for sugar-coating sentences to make them more palatable, attempting to build a criticism which would finally look more like a hidden admiration – no! none of that – he was absolutely upfront about issues in science and scientific community that bothered him. Some of these pieces could arguably be considered gems in scientific writing. No matter how successful he was in the lab, he had many things to read and say and talk about outside of it and was quite vibrant in doing so. In one Loose Ends issue, while delivering an argument for why there might be some basic fallacies in looking at biological problems from a theoretical physicist’s point of view (which was quite fashionable in those days), he writes: 

“I pointed out that if I took Professor Eugene Wigner (a theoretical physicist) and decomposed him into an ensemble of elementary particles, the chances of these reassembling into the same Professor Wigner, complete with accent, were zero and would indeed require a miracle. But Professor Wigner and other biological organisms are not made by condensation in a bag of elementary particles, but by some very special processes that are, of course, consistent with the laws of physics but could not easily be directly derived from them. The trouble with physics is that its deepest pronouncements are totally incomprehensible to almost everybody except the deepest physicists, and while the pronouncements may well be absolutely true, they are all pretty useless if my aim is to understand Escherichia coli.”

Centaur Biology; Loose ends, July 1, 1997

He then seemingly went on to bash certain sects of evolutionary biologists and theoretical physicists who claimed to have made an impact in biology; in his words, by a ‘handwaving process’ – 

“it is the detail that counts, and it counts because that is what natural selection had to accomplish for there to be anything at all. We want to know which genes are turned out and exactly where and precisely when. To view natural selection as a kind of handwaving process that seeks refuge in glorious generalities when it cannot solve problems, is the anthropomorphic reflection of our own insufficiencies.”

Centaur Biology; Loose ends, July 1, 1997

It is worth mentioning that some of his writing had less venom and sensation; sometimes he, indeed, ceased to be a provocateur and touched upon sharing his wisdom and providing advice, too, to his younger counterparts – 

“Survival in science, and especially in biology, takes something more than having a working body. The most important thing you can do is to stay out of phase. As fashions rise and then fall and then often rise again, it is important to be either half a wavelength in front or half a wavelength behind them. It does not matter which you choose. Although you might think that being ahead is much better, I should point out that it is also much harder; the fashions are almost certain to catch up with you and you will then be smothered. By contrast, staying half a wavelength behind gives you a more peaceful and productive life. You can deal with all the problems that the stampeding herds have left unsolved. Of course, in biology, it is often said that once the principle is grasped, the details can be left to others. I have said it myself. But I realize now that some problems cannot be solved without the details; the principle, while true, is vacuous.”

All the world’s a lab …and last, The survivor; False Starts, January 15, 2000

A decorated academic, vocal critic, and percipient mentor, Sydney Brenner loved to work and was quite evidently against retiring from it. He continued research even when he had to carry a tank of oxygen with him for his breathing problems. With his habitual wit, he described how he hated retirement parties and wanted to move on with more work: “[…]let anybody who may be planning a party for me know that I would very much like a multiprocessor work station and an electron microscope as parting gifts. And now, if you will excuse me, I have to go and look for another job (A retiring fellow; Loose Ends, May 1, 1997).”