The sui generis Sydney Brenner

Sydney Brenner died on April 5, 2019, at age 92. His fame arose from three domains in which he operated with uncommon intellectual vibrancy. First were his prescient ideas and breakthrough experiments that defined the DNA genetic code and how the information it contains is transmitted into proteins. Second, in a later career, he developed a model organism, the roundworm Caenorhabditis elegans, to determine how the cells of an animal descend, one by one, along pathways of increasing specialization. Last was his beguiling skill as an intellectual sharpshooter, often surprising colleagues by the immediacy of his “take” of a problem, even ones somewhat beyond his ken. He always was very swift to the core point and instant with a wise reply.

Sydney Brenner, 1927–2019. Image courtesy of Science Photo Library/James King-Holmes.

Even though most of Brenner’s career was about the gene, it is to be emphasized that he was a keen biologist from the start. As an undergraduate at the University of Witwatersrand, South Africa’s top university, he strayed from his premedical curriculum and became adept at looking at various protozoa and culturing them in the laboratory. He also got keen about meiosis and wrote a brief report in Nature on the high frequency of multipolar spindles, a biological oddity he found in the sperm of the South African jumping shrew, Elephantulus (1). Captivated by chromosomes and genes at this early stage, he then read publications of Cyril Hinshelwood at Oxford, a chemist turned bacteriologist. Winning a scholarship to attend Oxford, it was with Hinshelwood that Brenner’s fascination with the gene was catalyzed into full action. There, he did important work on how phages can go into transient dormancy. It seems likely that in doing these experiments, he came to perceive that DNA can be active or silent, a concept that had arisen elsewhere, but this was likely his first intimation.

Brenner might have continued working with bacterial viruses, a field being revolutionized at the time by the former physicist Max Delbruck, or he might have gone back to his beloved protozoa. But something else happened: A visitor arrived.

A scientist named Jack Dunitz from Caltech came to Oxford. He was an expert on protein structure, and because his forte was the method of X-ray diffraction of crystallized proteins, he also happened to be very tuned in to the ongoing work of James Watson and Francis Crick in Cambridge. Dunitz took Brenner to Cambridge to see the double helix that Watson and Crick had come up with. This moment in Brenner’s career has not always been adequately conveyed by historians, but I believe it was huge.

Of course, that trip up to Cambridge had a second impact that was also powerfully catalytic and enduring: Sydney and Francis Crick met. Much has been written about the intellectual intensity of their decades long resonance, and if I were to have one wish that an angel could descend and offer me, it would be to have been a fly on the wall of the office that they shared.

The double helix was done, but what next? One project involved Mahlon Hoagland, the codiscoverer of transfer RNA, which Crick had predicted but thought might only need to be three nucleotides long (okay . . . a genius can be off by ∼25 and get away with it). Transfer RNAs are small molecules that translate DNA coding into protein by each one of them connecting to and bringing into the protein synthesis machine a particular amino acid, the building blocks of protein, one by one. Hoagland and Crick worked away in an attic laboratory at the Molteno Institute in Cambridge, grinding up rat livers to seek the enzymes that hook adenosine 5′-triphosphate–activated amino acids onto transfer RNA. It was a complete bust. Sydney watched this and thought that the better approach was genetics. His observation of this was, I think, again one of those activities outside his own laboratory that he monitored with a keen eye, both hopeful and skeptical. In this particular case, it fueled his constitutional talent for “finding another way.”

In what is perhaps one of the most elegant series of experiments ever conducted in molecular biology, and far more elegant as cerebral foreplay and design than the discovery of the double helix, Brenner, working with Crick, discovered that the four letters in DNA—A, C, G, and T—are “read” in sets. Brenner and Crick observed how this affected the resulting protein encoded by this gene. The astonishing power of this series of experiments was boosted by the fact that Brenner had previously conducted an analysis that convinced him that whatever this genetic code was, the letters specifying each amino acid in a protein’s linear sequence could not be overlapping whatever number of letters were specifying one of the 20 amino acids (2). How did he get this? He looked at the limited amino acid sequences then at hand and astutely recognized that the frequency of the same two amino acids appearing consecutively was too low to be explained by an “overlapping code” in which, for example, the (then hypothetical) DNA letters AAA coding for lysine (this discovered later) should give lysine-lysine whenever there are four A’s in a row in the DNA. From an epistemological perspective, in this insight, Brenner had helped advance the concept that however it was achieved, there was something “colinear” between the sequence of letters in DNA and those in the encoded protein, as prescient experiments by Charles Yanosfsky had predicted.

Each year, when I teach the genetic code paper (3), I worry that the students won’t “get it.” But they do, and it is great to see. They sense the dialectical construct, and maybe they also sense that this, or some of it, is missing from all of the modern era papers they are assigned to read. And in these classes, I always make another point. The authors “fessed up” that their experiments had not really proven that the code has three letters, mentioning that it could be a hextet code or, in principle, one based on any factor of three. The students like this too, and say things like “Wow, they were very smart.” Brenner has left us so many things like this.

But, at this point, Brenner was not finished with the genetic code. In further studies, he confirmed that the code was manifest as a collinearity between the gene and protein (4). But that still not was enough for his agile mind. He went on to discover three so-called nonsense elements in the code that cause termination of protein synthesis and revealed how their undesirable action is offset (5).

After all this, a mind as uncommon as Sydney Brenner’s didn’t go into cruise control. Amazingly, at the very same time he was working with Crick on the genetic code, he and collaborators codiscovered messenger RNA (6). This was another Sydney Brenner tour de force. He sensed that infection of bacteria by a virus, known to result in a shutdown of the host cell’s RNA synthesis, would afford an opportunity to thus “see” the virus-produced RNA. Under judiciously selected experimental conditions, an RNA species indeed revealed itself and fulfilled all of the predicted properties of the long-sought “messenger” RNA. This great experiment also benefited from Mathew Meselson at Caltech, and from Francois Jacob visiting there from Paris, France. But the record shows that Brenner was the inspiration (7).

By this time, Brenner had become a legend and dozens of postdocs flooded into the Laboratory of Molecular Biology at the University of Cambridge. This hallowed hall of molecular biology is itself legend (8), and Sydney made it so on the genetics side, while Max Perutz and John Kendrew did so in structural biology. Many of the American postdocs who came wanted to work on RNA (9), but, by the late 1960s, some of these visitors sensed that Sydney was onto to something new and switched their projects. What was it?

The gene had been good to Brenner, and he had been good to its understanding. But let us recall his beginnings. Biology qua biology. So, sometime around 1965, he began to turn back to these roots. He was influenced by nearby colleagues like Lewis Wolpert and Peter Lawrence, as well as Francis Crick, all of whom were getting keen about the notion that embryonic development and cell differentiation might be explained by chemical gradients. This was not a new idea, but Wolpert had a particular knack for stating the problem in modern terms and he and Brenner seemed to resonate.

At this time, Brenner set off onto a period of incessant reading about many animals, thinking about which might be suitable for an attack on nothing less than how the embryo develops and, as an adult, performs its repertoire of functions. How he came to a nematode worm is full of the probative intellectual richness that was his métier. He wanted a creature that had complex behavior (i.e., had a brain), and thus was reactive to experience. He wanted one that could be cultured and was small enough to allow microscopic inspection. He read voraciously and sifted through many organisms as to their pluses and minuses. He then decided on C. elegans, a terrestrial soil niche worm. His colleague, John Sulston, traced out the cell lineages from the fertilized egg to the adult, and others in his group soon did so for the germline cells’ descent. This monumental achievement had been a holy grail in the science of embryology for more than a century, its frustrating challenge having led none other than Thomas Hunt Morgan to forgo marine embryos as intractable and move to the fruit fly.

For launching the transformatively impactful C. elegans program, Brenner was at last recognized with a Nobel Prize. Why he did not get this prize earlier is a long and intriguing story.

Every account of Sydney Brenner mentions his extremely agile sense of humor. I won’t recite the many quips we all enjoyed over the years, either from his rostrum at meetings or in the bar, but will simply say that I think this reflected an intellectual acumen of uncommon deftness, one that was aligned with grand arborization in the neuronal corridors of that amazing mind and constituting his genius.

Genius might best be defined as the capacity to recognize analogies. Sydney Brenner had this, and had a stronger dose than any scientist I have known. His like will not come along any time soon. We owe him so much. Who will now poke us for faulty logic or, on the upside, encourage us to push on and think outside the box when our idea seems doomed? What greater legacy could there be for anyone?