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Expanding the Genetic Code

Credit: (Neil Grant/Medical Research Council Cambridge)

The best career advice Jason Chin ever received came from an organic chemistry professor, biological chemist John Sutherland, who joined Chin recently as a colleague at the Medical Research Council Laboratory of Molecular Biology (LMB) in Cambridge, U.K. Chin, who was studying for a B.A. in chemistry at the University of Oxford, was fascinated with the idea that a set of principles could explain how the world is built up from its constituent elements. But Chin says he found Oxford's chemistry curriculum "incredibly traditional," and he soon became interested in how the principles of chemistry could be applied to living systems. Sutherland's advice: Don't limit yourself to what gets covered in class. Sutherland told Chin, "If you look at the periphery, this is where there is the most scope for discovery."

Chin has never really stopped to ponder whether his research goals are too ambitious -- too risky -- for a starting principal investigator.

Today, Chin, a tenured group leader, uses his knowledge of chemistry and his creativity to probe and sometimes remake central tenets of biology. As a postdoc, he equipped eukaryotic cells with the machinery needed to synthesize proteins that contain amino acids that aren't on the short list nature draws from. More recently, he's been altering the genetic code that organisms have used for billions of years to translate genetic information into proteins.

Seeking the unexplored

After earning his B.A., Chin took on a master's degree research project in Sutherland's lab, using genetic engineering to get bugs to biosynthesize an antibiotic called cephalosporin. "I knew Jason had the potential to excel before I took him on as a Masters student," Sutherland writes in an e-mail to Science Careers. "What impressed me most about him when he then worked with me was his almost immediate appreciation of the power of evolutionary methods in chemical biology research. He also had the ability to see the big picture rather than focus too much on details."

With a Fulbright scholarship in hand, Chin set off, in 1996, to work on a Ph.D. at Yale University. There, he joined the lab of Alanna Schepartz, developing chemical tools for studying and manipulating protein-DNA interactions within cells. Although he was a chemistry student, he took mostly graduate biology classes. "By the end of the first year, I was equally trained in biology and chemistry," he says.

In the Schepartz lab, Chin designed one of the first functional miniature proteins. He extracted from a natural protein a group of amino acids responsible for DNA recognition and grafted them onto a smaller, helical protein scaffold. The work required combinatorial biology techniques, which were not available in the lab at the time. He set it all up, learning from books. "That was quite tough as a Ph.D. student," Chin says -- but it taught him to be self-sufficient and to establish solid foundations for his work. He also learned to follow his curiosity whatever the cost.

Chin enjoyed the project -- until he cracked it, at which point he started to look for a new area. Once you solve a problem, he says, "You have two choices: either you can keep solving the same problems or find new problems that are exciting," Chin says. He chose the latter course. Upon graduating in 2001, he sent off a packet to Peter Schultz at The Scripps Research Institute in San Diego, California, containing his curriculum vitae, a couple of recommendation letters, and a letter describing the work he intended to do during a postdoc in Schultz's lab.

Unnatural acts

All the proteins found in nature are products of complex cellular machinery, which assemble the constituent amino acids according to a genetic blueprint. The ribosome translates genetic information using a dictionary -- or genetic code -- that is common to all living species. Small molecules called transfer RNAs assist the ribosome, each carrying an amino acid corresponding to a particular triplet of genetic letters. The ribosome reads the genetic blueprint, looking at three letters at a time, and calls in a matching transfer RNA to knit amino acids into a growing chain of peptides.

The genetic code is an extraordinary thing, but it has a limited vocabulary. It is able to translate DNA into just 20 standard amino acids. In 2001, Schultz changed this, supplementing Escherichia coli's translational machinery so that it could incorporate a novel amino acid into proteins. He tweaked the enzyme that normally loads amino acids onto transfer RNAs so that an unnatural amino acid could be loaded onto a mutated transfer RNA -- one that corresponds to a genetic triplet that normally orders the ribosome to stop translation. Instead, the transfer RNA added the new amino acid to the protein, and the ribosome continued translating.

Chin used this approach to force E. coli to insert novel amino acids that form strong chemical bonds with nearby proteins when light shines on the cells. Today, "people use these technologies directly to tease out information about how proteins are interacting," Chin says.

But "what would be really transformative," Chin surmised, would be to get complex, eukaryotic cells to produce proteins containing unnatural amino acids. He dedicated the rest of his postdoc to making this happen. Although the same principles were involved as for prokaryotes, the translational machinery is so different that a new transfer RNA-enzyme pair had to be found. It was "challenging to do," Chin says -- but he and Ashton Cropp, another postdoc who is now an assistant professor at the University of Maryland, College Park, figured out how to do it.

Becoming independent

Chin returned to the United Kingdom in 2003 with a tenure-track position at LMB. He had secured the position just a few months into his postdoc at Scripps, but staying longer in the United States allowed him to come back with a clearer idea of what he wanted to be working on next.

Before moving to Cambridge, he spent a few months back at Yale, waiting for his fiancé to finish her Ph.D. so they could go to the United Kingdom together. While he was there, Chin attended a lecture by Venkatraman Ramakrishnan of LMB. Ramakrishnan (who was awarded a Nobel Prize for the work in 2009) described in molecular detail how ribosomes decode genetic information. "It was amazing," Chin says. "In chemistry, … we have good control over how to make small molecules," but "we don't know how to assemble polymers of defined sequence. The ribosome is a paradigm of a molecular assembler."

Chin says the lecture inspired him to ask, "What will it take to convert the ribosome from something that makes [natural] proteins into something able to assemble … new, different types of chemical entities?" So after he arrived in Cambridge and assembled a team, they went to work on engineering new translational machinery that would allow living cells to produce proteins that contain none of the amino acids nature uses.

Until then, just one type of amino acid could be added into proteins at a time. Chin started by making this process more efficient, complementing E. coli's natural translational machinery with an artificial ribosome. He then had to figure out how to insert more than one unnatural amino acid into the same protein. To do this, he had to overcome a limitation imposed by the natural genetic code: most of the available triplets were already taken, corresponding to a specific, natural amino acid. There was little room to add more. So Chin set out to write an entirely new genetic code based on quadruplets of genetic letters instead of triplets. Using this approach, he's already made living cells that produce proteins containing two distinct, novel amino acids. It's a crucial second step toward producing entirely unnatural proteins.

Chin is also continuing to pursue new applications of the technology he's developing. "We have also got really interested in how, by putting new amino acids in proteins, you can address … problems in biology that would be impossible to address otherwise," he says. For example, the modification of natural amino acids in the proteins that package our genomes, by natural means, has long been known to affect which genes are expressed and when, but how this works remains unclear. Chin has been able to study these processes by adding such modifications to the packaging proteins at will.

Strategy versus creativity

In the last couple of years, Chin's group has grown from four to 15 people. He's obtained a grant from the Human Frontier Science Program as well as a Starting Grant from the European Research Council. His work has been recognized with a string of awards, most recently a gold medal from the European Molecular Biology Organization.

Credit: Christine Panagiotidis/EMBO
Jason Chin at the EMBO awards ceremony.

Chin has never really stopped to ponder whether his research goals are too ambitious -- too risky -- for a starting principal investigator; he was focused too passionately on the research to consider career implications. But he did design his research plan to minimize those risks. He put together a 5-year research plan consisting of independent modules that, if successful, would each be "completely new and useful in its own right" while also feeding into the larger success of the lab. That way, "even if we had not got the first bit to work, we still had many other things to do."

Whether it's due to nature or nurture, Chin has a propensity for uniqueness and a desire to put an individual, even artistic, stamp on his work. "I find it a bit depressing when people choose to work on things where … if you don't do it, some other people will do it," he says. "Whereas in science ideas have to be articulated in concrete terms, the great thing about writing and other forms of art is that they contain ideas that are at the edge of what we know how to articulate," says Chin, a life-long enthusiast of British literature. Feeling comfortable with that helps you explore scientific paradigms that are conceptually new, he adds.

Creativity, Chin believes, arises naturally from "just being engaged in life." As you make new discoveries, "your horizons expand and expand and you start seeing connections between all sorts of things," he says. "That's probably quite a good model in general for what to work on independently as well, because you absorb things from different areas, and then you synthesize them in a way that's uniquely your own."

Elisabeth Pain is Science Careers' contributing editor for South Europe.

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