A Book Review of

My Life in Science

Book by SYDNEY BRENNER (as told to LEWIS WOLPERT)

In Singapore, where my own life in science began, Sydney Brenner is a prominent name. His pivotal role in establishing biotechnology as one of Singapore’s economic pillars earned him the first honorary citizenship ever awarded by the city-state. In 1984, he advised then prime minister Lee Kuan Yew to build a research institute to train young molecular biologists. Lee had doubts, remarking that Singapore was a nation of technicians, not scientists. But Brenner candidly retorted, “Prime minister, if you don’t do something like this, you will remain a nation of technicians.” Thirty years after, I was spending the majority of my time as a Ph.D. student in Biopolis, Singapore’s hub of biomedical research institutes that Brenner himself named. Eight more years later, I reconnected with Brenner by reading his personal account “My Life in Science”. 

Reading Brenner, to me, was nostalgic. My very first research project (as an undergraduate) was done in the laboratory of Dr. Koh Cheng Gee, who, you see, was a student of Brenner. While Brenner had a firecracker personality, Dr. Koh is quite the opposite. As Lewis Wolpert puts it, Brenner “was an indefatigable talker at every opportunity… with stories he made up as he went along. Generously laced with jokes… he went without a break from one register to another.” Dr. Koh, on the other hand, would speak softly, her energy tranquil, steadfast. But beneath her calm was a fiery interest in discovery that she shared with her mentor. When she asked me to investigate the relationship between cell death and the cell cycle, her bubbling enthusiasm on the topic was infectious. Despite my naivete, she encouraged me to try out my own ideas. I imagine that her mentorship drew from Brenner. “I’m a great believer in the power of ignorance,” Brenner says. “I feel that one of the problems about being an experienced scientist in a particular field is that it can curtail creativity… The best way to prepare for a heroic voyage in science is to just start.” And Dr. Koh pushed me to just start.

Reading Brenner, to me, was refreshing, not only because it brought me back to my scientific roots, but also because his calculated balance of theory and experimentation, his volatile mixture of logic and creativity made the scientific process electrifying. My favourite instance was when he describes finding C. elegans, the humble worm that Brenner transformed into one of the most influential model organisms in biology. This did not happen by chance, believing that “the choice of an experimental object remains one of the most important things to do in biology… the diversity in the living world is so large, and since everything is connected in some way, let’s find the best one.” Brenner was interested in the intricacy of the brain and wanted to obtain a complete wiring map. “Modellers are always confronted by sceptics,” he says. If they ask: how do you know there isn’t another wire?, “you need to be able to say, there are no more wires. We know all the wires.” Such an exhaustive map required knowing how every cell is physically connected with another. Feasible with the electron microscope, but its tiny observation window required an even tinier organism. Brenner decided that small worms called nematodes were the answer. But among them, he wanted one that could be ‘cut and fixed properly’ for imaging, that has ‘a beautiful sex life’ (hermaphrodite worms can breed with themselves, making genetics easy), that has a rapid life cycle, that could be stored by freezing, and so on. In search of worms, he asked everyone he knew to bring back some soil when they travelled, and by filtering through his newfound collection, he decided on C. elegans, which humorously enough, has elegans in its name! Today, it is the most complex organism whose developmental cell trajectory (from the unicellular egg to all of its 959 somatic cells; Figure 1) and nervous circuitry (all 6,334 neural connections) are both fully mapped¹–a true marvel of biological research.

Figure 1:  Anatomy of the hermaphrodite C. elegans (top) and its complete cell lineage from zygote to adult (below).

Photo credit: Wormbook.org, the online review of C. elegans biology, and Wormatlas.org, a database featuring behavioral and structural anatomy of C. elegans and other nematodes.

Brenner’s appreciation and application of the vastness of life returned me to a recent fond memory. Under Maui’s starry sky, after trekking the Mars-like terrain of Haleakalā, three colleagues and I found ourselves discussing: if extraterrestrial life ever were to find us, what would happen? Would they be hostile? If we are seen as competition for resources, then probably yes. This assumes that the ‘selfish gene hypothesis’ applies to them–what if it doesn’t? Let’s say they all come from a primordial soup and, unlike life on Earth, are not driven by the propagation of its species. Souplings, we called them (Figure 2). Maybe their motive does not matter, as their entrance would destroy the ecosystem’s balance and lead to our inevitable demise. This conversation, albeit inebriated, was a fun theoretical exercise that ultimately boiled down to a question larger than us: how would the natural world, governed by Darwin’s survival of the fittest as we know it, react to an organism detached from this evolutionary law? Upon my return home, I wondered why we, as scientists, don’t do this more often? Why not zoom out of our specialised research niches and wander outside? Go crazy. Go stupid. Brenner’s magic circle of colleagues, the RNA tie club, did just that: “The one thing that really characterised our conversations is that we never restrained ourselves in anything we said – even if it sounded completely stupid!”

Figure 2:  Souplings as depicted by Anita Gola (top-left), Alain Bonny (top-right), Irina Matos (bottom-left) and myself (bottom-right).

Follow them at @anita__gola and @DrIrinaMatos on Twitter!

I always thought that if I want to be an independent investigator in today’s academic atmosphere, I must create my own unique bubble, tackle a question that nobody else is answering. I never liked this idea of hyperspecialization. I think that the most exciting questions are the most fundamental ones, and Brenner built a career focusing on just that. Molecular biology “really crystallised all the problems, all the issues, into the following question. How does the DNA structure map onto the amino acid sequence? That is, what is the genetic code?” This fundamental question was initially hindered by the revelation of the double helix – DNA structure of intertwined strands – which made unwinding the chains seem impossible. On this, Brenner formulated what he called a ‘don’t worry hypothesis’: there must be enzymes that do it. This powerful tool allowed him “not of course to ignore facts, but to deal with what seem to be difficulties later, rather than rejecting the hypothesis out of hand as being impossible.” His idea turned out to be right in the form of DNA helicases. For protein folding, he simply jested, “It’s done with no hands!”. 

What made Brenner carefree made him successful. In his ease in navigating science’s sphere, instead of creating his own unique bubble, he invited the best minds he knew to share one. Throughout the book, he anecdotes both serious conversations and silly encounters with friends and colleagues as they together crack the genetic code, whether at work or at a seaside holiday. Brenner spoke of them fondly, especially of Seymour Benzer and Francis Crick, who, of course, like Brenner, end up becoming legends that shaped modern biology (Benzer for describing the structure of the gene with his studies in phage, Crick for the famous double helix). “Science has to operate as a group, as a social unit,” Brenner states, acknowledging the value of sharing ideas, of conversation. “When an idea forms in my mind it’s usually at least fifty percent wrong,” he says, but with “the social interaction, the companionship that comes from two people’s minds playing on each other,” you can refine it into the right idea. 

Is this still possible today, when success is individualistic, self-interest is encouraged – ideas are kept secret so as to not get ‘scooped’? Brenner comments about this too: about the scientist’s motivation being “to win a lot of prizes and get a lot of money”, about sensationalism, such that you can’t publish a paper unless you do science the trendy way, about the narrow-minded nature of the research funding system that forces scientists to endlessly justify their work, about the scientist who falls in love with an idea and will do anything to prove it, even when it might be wrong. These grievances are palpable in the current academic atmosphere and for me, suck all the joy out of research. They leave a bitter taste, but Brenner’s book offers a chaser. In it, he says, “I’ve always felt that science makes completely contradictory demands on the people who work in it. It asks you to be highly imaginative, yet it asks you to put on blinders and drive through brick walls if necessary… It asks you to be passionate about invention, but it also asks you to be ruthless and cut off your own hand if it comes to that… But really, the great thing about science is that you can actually solve a problem. You can take something which is confused, a mess, and not only find a solution, but prove it’s the right one.“ 

Reading Brenner, to me, was finding solace. It reminded me of why I chose science in the first place, and why I still do it to this day. 

¹Numbers are for the hermaphrodite worm. Numbers for males (also fully mapped) are even higher.