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The Greatest Adventure In The World

Sim Shuzhen | October 14, 2015 | 

In 1953, Francis Crick and James Watson, two scientists working at the University of Cambridge in the UK, deduced the molecular structure of DNA, proposing a double helix formed by paired chains of the nucleotide bases A, C, G and T. 

Sydney Brenner, then a 26-year-old PhD student at Oxford University, describes seeing their model of DNA for the first time as a watershed moment in his scientific career. At that point, the question of how a mere four bases could encode the information required for cells to make all the proteins necessary for life—the genetic code—was as yet unsolved. In the early 1960s, Professor Brenner’s role in deciphering the genetic code helped lay the foundation of modern molecular biology. 

Few scientists make their mark on even one specialised field of research. Several years later, Professor Brenner’s pioneering use of the nematode worm Caenorhabditis elegans (C. elegans) as a model for understanding human biology revolutionised research in genetics and developmental biology, and in 2002 earned him the Nobel Prize in Physiology or Medicine. 

Since 1983, in his capacity as a trusted advisor to the Singapore government on scientific policy, Professor Brenner has been instrumental in establishing Singapore as a biomedical research centre of international repute. In 2003, Singapore conferred on him its inaugural Honorary Citizen Award, the nation’s highest form of state recognition for non-citizens. 

Today Professor Brenner, 88, is senior fellow at Singapore’s Agency for Science, Technology, and Research (A*STAR), and also holds senior faculty positions at the Salk Institute and the Howard Hughes Medical Institute in the US. “I’ve had a good long run in science,” he acknowledges. 

The genetic code and nematode worms 

Professor Brenner developed an interest inmolecular biology as a medical student in the 1940s in his native South Africa. Keener on research than medical practice, he moved to the UK in 1952 for a PhD at Oxford. Then in 1956 he joined the Laboratory of Molecular Biology (LMB) at Cambridge, where he would share an office with Dr Crick for twenty years. 

In 1961, together with Dr Crick and others, Professor Brenner showed that the genetic code is composed of non-overlapping triplets—three bases, or a codon, encoded one amino acid, the basic building block of proteins. 

Turning next to the question of how information is transferred between DNA and proteins, Professor Brenner demonstrated the existence of messenger RNA, an unstable intermediate molecule that carries information from DNA in the nucleus to ribosomes—the cell’s protein making machinery—in the cytoplasm of the cell. 

Today, “DNA makes RNA and RNA makes protein” is considered the “central dogma” of molecular biology. But in the 1950s, the scientific establishment ridiculed the idea that DNA could carry all the information required for life. Professor Brenner had “to preach to the heathen”. 

In the late 1960s, Professor Brenner became interested in the genetics of how complex organisms grow, particularly in the development of the human brain and nervous system. Scientists often study model organisms—simple organisms that can be easily handled in the laboratory—to gain insights into the biology of more complex animals, such as humans. In genetics, for example, the fruit fly Drosophila melanogaster and the yeast Saccharomyces cerevisiae are widely-used model organisms. 

Professor Brenner recognised the potential of C. elegans, a one millimetre-long nematode worm with a transparent body and simple nervous system, for studying developmental biology. In a 1974 paper, he described important aspects of its genetics, along with methods for studying it in the laboratory, thus establishing it as a new model organism. 

Research on C. elegans blossomed. Scientists tracked the development of every single one of its 959 cells and mapped the wiring of its 302 neurons. By the early 1990s, scientists had started to sequence entire genomes of simple, single celled organisms—the first was the bacterium Haemophilus influenzae. 

In 1998, thanks to a consortium of researchers in the UK and US, C. elegans became the first multicellular organism to have its complete genome sequenced. Dubbed “nature’s gift to science” by Professor Brenner in his 2002 Nobel lecture, this humble organism has helped researchers understand fundamental cellular processes such as cell division, embryogenesis, ageing and cell death. 

Developing biomedical research in Singapore 

In 1983 the Singapore government, eager to diversify the country’s economy away from lowcost manufacturing, sought Professor Brenner’s advice on developing a biotechnology sector. He proposed setting up the Institute of Molecular and Cell Biology (IMCB) at the National University of Singapore (NUS) in order to train Singaporeans and provide research infrastructure. 

Inaugurated in 1987, the IMCB’s mandate was also to prove that Singapore, despite being a tiny population with little experience in basic research, could produce high-calibre scientific research. 

Professor Brenner ran a laboratory at the IMCB, and led efforts to study the genome of the Takifugu rubripes puffer fish—or fugu in Japanese. His team showed that the fugu and human genomes share similar blueprints, even though the former is about eight times smaller than the latter. 

Like C. elegans, the compact fugu genome is an ideal model for studying larger and more complex genomes. The IMCB enhanced its international reputation when it became a key member of an international consortium that in 2002 published a draft sequence of the fugu genome in Science, a journal. 

Professor Brenner is, understandably, tired of talking about his older achievements. But ask him about his latest endeavour, the Molecular Engineering Laboratory (MEL), set up in 2009 at the Biopolis, and his eyes light up. 

In the early, heady days of molecular biology, Professor Brenner and his fellow rebels at Cambridge did not accept students. “Who wants to be stuck with a student for three years when the field was changing almost every month?” he muses. “In a dynamic field you can’t maintain a project because a student has to get his PhD.” 

Today, under constant pressure to compete for grants and pass performance reviews, principal investigators (PIs, the heads of laboratories) tend to maintain large groups of graduate students and post-doctoral fellows, on whom they rely to produce the science. In the US, especially, this has resulted in a glut of PhD holders, without a corresponding increase in jobs for them. 

The entire system of academia, thinks Professor Brenner, is bad for scientific innovation. The bureaucracy stifles talent. “PIs have ceased to become scientists,” he worries. “They become managers and sit in offices all the time and have group meeting and so on. That’s not the way you create new science.” As employees of the PIs, students and “post-docs” also lack the independence to work on problems that really interest them. 

In a bid to liberate them, Professor Brenner established MEL. Here, freshly-minted PhDs are their own bosses. “You’re independent, but you’re also responsible,” he says. “If you’ve got ideas, you implement them. You really need to take it all the way through.” 

MEL is not only unique in its structure, but also in the scope of its research. It was the first place, Professor Brenner says, to institutionalise molecular engineering, an extremely broad, interdisciplinary field involving the design, manipulation, and synthesis of molecules for myriad applications. These proteins can be used to make materials with unique properties, for example, or chemical scaffolds that can be used to design better drugs. 

One area of research at MEL is biomimetics—a field in which the imitation or mimicry of nature is used to solve engineering problems. Here, the team is studying and designing potentially useful proteins from marine organisms. For instance, suckerin, the protein present in the sucker ring teeth of squid, could be used to make strong, flexible materials for applications ranging from reconstructive surgery to eco-friendly packaging. 

Others in the laboratory are developing molecular probes—molecules that exhibit a measurable change, such as emitting fluorescence, after interacting with other molecules. These are useful in a wide variety of industrial and research applications—monitoring chemical manufacturing processes, for example, or detecting a specific DNA sequence. 

MEL, Professor Brenner hopes, will nurture talented young researchers, whom he views as the biggest investment in the future that Singapore can make. “Ninety percent, maybe even more, of what goes on in research and development is essentially routine,” he says. “And that’s fine. But you also need the talent to do something new.” 

Constant reinvention, he thinks, is especially important for small countries like Singapore, which must keep creating new possibilities and opportunities for their people. It certainly helps that Singaporeans, in his opinion, are focussed on self improvement. MEL often loses talented research technicians to graduate programmes at top-notch universities. 

Singapore, Professor Brenner believes, like most of Asia, has a problem that cannot easily be solved by throwing money at it. “There is a lesion which is very bad, and that is respect for seniority,” he says. “People don’t ask questions in lectures. I think we’ve got to encourage the questioning.” 

The greatest adventure in the world 

For Professor Brenner, science has always been all consuming. “Work doesn’t start at 8 and finish at 5 and then you forget about it,” he says. “It goes on day and night. And of course it’s hard to keep a family life when most of the time you’re living in your own head.” 

Nevertheless, Professor Brenner and his late wife May raised four children, and were married for 58 years, until her death in 2010.

Professor Brenner believes that any sacrifices he has had to make pale in comparison to the excitement of discovery. “I think it’s the greatest adventure in the world to really know, at a given point, that you’re the only person in the world that knows something new,” he enthuses. “That’s a thrill that’s worth it.” 

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